100 Scientific Studies of the Enzyme:  Cathepsin

Record 1 from database: MEDLINE
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Title

Plasma cathepsin activity and reticuloendothelial phagocytic function during hemorrhagic shock.

Author

Loegering DJ; Carr FK

Address

 

Source

Circ Shock, 1978, 5:1, 61-71

Abstract

The present study evaluated two forms of hemorrhagic shock in terms of changes in plasma lysosomal enzyme activity, reticuloendothelial system (RES) phagocytic function, and plasma opsonic activity. Hemorrhagic shock was induced in rats by withdrawal of a fixed volume of blood equivalent to 3% body weight or by maintaining the arterial blood pressure at 40--45 mm Hg. Plasma cathepsin activity did not increase until after one hour of hypotension, and was increased 2.7-fold two hours after a 3% body weight hemorrhage and 11-fold after two hours at a blood pressure of 40--45 mm Hg. Phagocytic index and plasma opsonic activity were decreased in animals reinfused at 0, 30, or 120 minutes following a 3% body weight hemorrhage and in animals reinfused 0, 30, and 90 minutes following hemorrhage to a blood pressure of 40 mm Hg. There was a strong temporal relationship between the changes in phagocytic index and plasma opsonic activity; however, the decrease in RES function occurred earlier than the increase in plasma lysosomal enzyme activity. These results suggest that the depression of RES function during shock may be mediated, in part, by a deficit in circulating opsonic activity and that RES depression occurs prior to shock-induced cellular injury during hemorrhagic shock.

Language of Publication

English

Unique Identifier

78167657

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MeSH Heading (Major)

Cathepsins|*BL; Phagocytosis|*; Reticuloendothelial System|EN/*PP; Shock, Hemorrhagic|EN/*PP

MeSH Heading

Animal; Blood Pressure; Lysosomes|EN; Male; Opsonins|AN; Phagocytes|EN; Rats; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0092-6213

Country of Publication

UNITED STATES

Record 2 from database: MEDLINE
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Title

Proteolysis of factor V by cathepsin G and elastase indicates that cleavage at Arg1545 optimizes cofactor function by facilitating factor Xa binding.

Author

Camire RM; Kalafatis M; Tracy PB

Address

Department of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA.

Source

Biochemistry, 1998 Aug, 37:34, 11896-906

Abstract

The single-chain procofactor factor V is cleaved by thrombin (FVaIIa) at Arg709, Arg1018, and Arg1545 and by a variety of other proteases to generate a cofactor species with various levels of cofactor function. Having demonstrated previously that monocyte-bound forms of cathepsin G and elastase cleave and activate factor V, studies were initiated here using purified proteins to probe factor V structure/function. Electrophoretic, Western blotting, and amino-terminal sequence analyses revealed that cathepsin G cleaves factor V at several sites (Phe1031, Leu1447, Tyr1518, and potentially Tyr696), ultimately generating an amino-terminal 103 kDa heavy chain and a carboxy-terminal 80 kDa light chain (FVaCG). Elastase also cleaves factor V at several sites (Ile708, Ile819, Ile1484, and potentially Thr678), generating a cofactor species, FVaHNE, with an amino-terminal 102 kDa heavy chain and a carboxy-terminal 90 kDa light chain. Incubation of FVaIIa with either cathepsin G or elastase resulted in cleavage within the heavy chain, releasing peptides of approximately 2000 and approximately 3000 Da, respectively, generating FVaIIa/CG and FVaIIa/HNE. The functional activity of each cofactor species was assessed either by clotting assay or by employing a purified prothrombinase assay using saturating amounts of factor Xa. Significant differences in cofactor function were observed between the two assay systems. Whereas FVaIIa, FVaCG, FVaIIa/CG, FVaHNE, and FVaIIa/HNE all had similar cofactor activities in the purified prothrombinase assay, FVaCG and FVaHNE had no cofactor activity in the clotting-based assay, and FVaIIa/CG and FVaIIa/HNE had approximately 30-35% clotting activity relative to FVaIIa. These disparate results led us to examine the binding interactions of these cofactors with the various prothrombinase components. Kinetic analyses indicated that FVaIIa (Kd(app) = 0.096 nM), FVaIIa/CG (Kd(app) = 0.244 nM), and FVaIIa/HNE (Kd(app) = 0.137 nM) bound to membrane-bound factor Xa much more effectively than FVaCG (Kd(app) = 1.46 nM) and FVaHNE (Kd(app) = 0.818 nM). In contrast, studies of the activated protein C (APC)-catalyzed inactivation of each of the factor V(a) species indicated that they were all equivalent substrates for APC with no differences observed in the rate of inactivation or the cleavage mechanism, suggesting that APC interacts with the light chain at a site distinct from factor Xa. The Km values for prothrombin, as well as the kcat values for each of the FV(a) species, were all similar (approximately 0.25 microM and approximately 1900 min-1). In addition, kinetic analyses indicated that whereas FVaCG and FVaHNE exhibited a slightly reduced ability to interact with phospholipid vesicles (approximately 2-3-fold), the remaining FV(a) species assembled equally well on this surface. Collectively, these data indicate that FVaCG and FVaHNE have a diminished capacity to support factor Xa binding; however, cleavage at Arg1545 and removal of the extended B-domain in these cofactors restore near-total factor Xa binding. Thus, cleavage at Arg1545 optimizes cofactor function within prothrombinase by facilitating factor Xa binding to membrane-bound FVa.

Language of Publication

English

Unique Identifier

98384156

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MeSH Heading (Major)

Arginine|*ME; Cathepsins|*ME/PH; Factor V|CH/*ME; Factor Xa|*ME; Pancreatic Elastase|*ME/PH

MeSH Heading

Binding Sites; Blood Coagulation Tests|MT; Catalysis; Enzyme Activation; Factor Va|ME; Human; Hydrolysis; Kinetics; Membranes, Artificial; Phosphatidylcholines|ME; Phosphatidylserines|ME; Protein Binding; Protein C|ME; Prothrombin|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-2960

Country of Publication

UNITED STATES

Record 3 from database: MEDLINE
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Title

Human leucocyte elastase and cathepsin G: structural and functional characteristics.

Author

Travis J; Giles PJ; Porcelli L; Reilly CF; Baugh R; Powers J

Address

 

Source

Ciba Found Symp, 1979, :75, 51-68

Abstract

Two of the major enzymes present in an released from neutrophil granulocytes are the endoproteinases elastase and cathepsin G. While the former is believed to be one of the major causative agents responsible for tissue destruction in emphysema and rheumatoid arthritis, little is known about the function of cathepsin G. We have recently developed simple procedures for isolating the isoenzymes of each type of proteinase as well as for their specific controlling plasma inhibitors. We have also prepared synthetic substrates and inhibitor analogues. Some sequence studies have been initiated and the results indicate homology of these enzymes not only with each other and with the pancreatic proteinases but also between cathepsin G and proteolytic enzymes present in muscle and mast cell tissue. Significantly, both types of enzyme can degrade the structural protein myosin, as well as elastin and proteoglycan. However, their relative importance in muscle protein turnover or muscle disease has not yet been clarified.

Language of Publication

English

Unique Identifier

81089733

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MeSH Heading (Major)

Cathepsins|*/AI/IP/ME; Leukocytes|*EN; Pancreatic Elastase|*/AI/IP/ME

MeSH Heading

Amino Acid Sequence; Human; Isoenzymes|IP; Molecular Weight; Proteins|ME

Publication Type

JOURNAL ARTICLE; REVIEW

ISSN

0300-5208

Country of Publication

NETHERLANDS

Record 4 from database: MEDLINE
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Title

Proteoglycan-degrading enzymes. A radiochemical assay method and the detection of a new enzyme cathepsin F.

Author

Dingle JT; Blow AM; Barrett AJ; Martin PE

Address

 

Source

Biochem J, 1977 Dec, 167:3, 775-85

Abstract

1. Polyacrylamide beads containing entrapped 35S-labelled proteoglycan molecules have been prepared. 2. The measurement of release of radioactivity provides an extremely sensitive assay for proteoglycan-degrading enzymes, including proteinases and hyaluronidase. 3. The amount of label released is a logarithmic function of enzyme concentration or time of incubation. Experiments were made in an attempt to explain this. 4. Assays were made by the new method at several pH values, and with the inclusion of inhibitors to identify the proteoglycan-degrading enzymes of rabbit ear cartilage. 5. A previously undescribed proteinase active against proteoglycan at pH4.5 but unaffected by pepstatin, was discovered. The enzyme was named cathepsin F, and was partially purified and characterized; it was detected in human articular cartilage.

Language of Publication

English

Unique Identifier

78103158

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MeSH Heading (Major)

Cathepsins|AI/*AN/IP; Proteoglycans|*

MeSH Heading

Acrylamides; Animal; Cartilage|EN; Chromatography, Gel; Human; Hydrogen-Ion Concentration; IgG; Pepstatins|PD; Rabbits; Sepharose; Subcellular Fractions|EN; Sulfur Radioisotopes; Viscosity

Publication Type

JOURNAL ARTICLE

ISSN

0006-2936

Country of Publication

ENGLAND

Record 5 from database: MEDLINE
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Title

Cathepsin D: ultra-immunohistochemical localization in dentinogenesis.

Author

Nygren H; Persliden B; Hansson HA; Linde A

Address

 

Source

Calcif Tissue Int, 1979, 29:3, 251-6

Abstract

Cathepsin D was purified from rat liver using a new affinity chromatographic method, based on the coupling to the specific inhibitor pepstatin. This preparation was used for the production of specific antibodies from rabbit. The purified IgG fraction was conjugated to horseradish peroxidase in a two-step coupling procedure and used for electron microscopic immunohistochemistry of the odontoblast-predentine region of the rat incisor. Precipitates, indicating the presence of cathepsin D, were seen in the odontoblast, odontoblast process, and in the extracellular unmineralized matrix, the predentine. The observations are discussed in relation to proteoglycan degradation at the mineralization front simultaneous with crystal formation, and in relation to the function of lysosomal enzymes in the turnover of connective tissue.

Language of Publication

English

Unique Identifier

80089530

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MeSH Heading (Major)

Cathepsins|*AN/IP; Dentinogenesis|*; Incisor|*EN/UL; Odontoblasts|*EN/UL

MeSH Heading

Animal; Chromatography, Affinity; Immunoenzyme Techniques; Liver|EN; Rats

Publication Type

JOURNAL ARTICLE

ISSN

0171-967X

Country of Publication

UNITED STATES

Record 6 from database: MEDLINE
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Title

Inhibition of human liver cathepsin L by alpha 2 cysteine-proteinase inhibitor and the low-Mr cysteine proteinase inhibitor from human serum.

Author

Pagano M; Esnard F; Engler R; Gauthier F

Address

 

Source

Biochem J, 1984 May, 220:1, 147-55

Abstract

The inhibition of human liver cathepsin L by two specific proteinase inhibitors present in human serum, namely alpha 2 cysteine-proteinase inhibitor and the low-Mr cysteine-proteinase inhibitor, was studied. Kinetic parameters, including inhibition constants (Ki) and rate constants for association and dissociation (k+1 and K-1), were determined. The values found are consistent with a possible physiological function of these inhibitors to control cathepsin L activity. Furthermore, a transfer of active proteinase from the complex with either cysteine-proteinase inhibitor species to alpha 2-macroglobulin was demonstrated in vitro. Given the rate of dissociation of both cathepsin-L-cysteine-proteinase inhibitor complexes, a function of transitory inhibitor can therefore be hypothesized for these proteins and might then provide an explanation of the clearance of lysosomal proteinases.

Language of Publication

English

Unique Identifier

84256619

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MeSH Heading (Major)

Cathepsins|*AI; Liver|*EN; Protease Inhibitors|*PD; Sulfhydryl Compounds|BL/IP/*PD

MeSH Heading

Binding Sites; Human; Kinetics; Lysosomes|EN; Macromolecular Systems

Publication Type

JOURNAL ARTICLE

ISSN

0264-6021

Country of Publication

ENGLAND

Record 7 from database: MEDLINE
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Title

Cathepsin B from human renal cortex.

Author

Gounaris AD; Slater EE

Address

 

Source

Biochem J, 1982 Aug, 205:2, 295-302

Abstract

Cysteine-proteinase activity was observed in homogenates of human-cadaver renal cortex. This activity co-purified with renin enzymic activity until separation by aminohexyl-Sepharose--pepstatin affinity chromatography. The cysteine proteinase was purified 1780-fold after the following successive chromatographic procedures: Sephadex G-75, DEAE-cellulose DE-52, and an organomercurial affinity resin. The proteinase activity was dependent upon activation by thiol-containing compounds such as dithiothreitol, as well as by EDTA, and was inhibited by the thiol-group-specific alkylating reagents iodoacetic acid and N-ethylmaleimide. DE-52 cellulose chromatography resolved the cysteine proteinase into two components. On the basis of molecular size (26 000 daltons), activity as a function of pH, stability as a function of pH, substrate specificity and thermal lability, the major component (95%) has been identified as cathepsin B. The DE-52 cellulose elution pattern of the minor component (5%) is suggestive of cathepsin H [Schwartz & Barrett (1980) Biochem. J. 191, 487-497] Enzymic activity was determined with synthetic substrates, in particular alpha-N-benzoyl-DL-arginine 2-naphthylamide (Bz-Arg-NNap), thus precluding the detection of cathepsin L [Kirschke, Langner, Wiederanders, Ansorge, Bohley & Broghammer (1976) Acta Biol. Med. Germ. 35, 285-299]. Inhibition by dimethyl sulphoxide was observed in the determination of Km = 7.0 +/- 0.4 mM for the substrate Bz-Arg-NNap, and care must therefore be taken in the preparation of substrate solutions.

Language of Publication

English

Unique Identifier

83048214

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MeSH Heading (Major)

Cathepsins|AI/*IP/*ME; Kidney Cortex|*EN

MeSH Heading

Chromatography, Affinity; Chromatography, Gel; Chromatography, Ion Exchange; Dimethyl Sulfoxide|PD; Electrophoresis, Polyacrylamide Gel; Human; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-2936

Country of Publication

ENGLAND

Record 8 from database: MEDLINE
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Title

Specificity and some physical properties of cathepsin D from bovine uterus and dental pulp.

Author

Schwabe C

Address

 

Source

J Dent Res, 1975 Mar, 54:2, 371-7

Abstract

The action of uterine cathepsin D on the insulin A-chain (S-sulfo) and porcine glucagon was compared with the action of bovine dental pulp cathepsin on the same substrates. Differences observed with respect to molecular and catalytic properties suggest that different gene products (coding for the same function) are used during cell differentiation.

Language of Publication

English

Unique Identifier

75115257

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MeSH Heading (Major)

Cathepsins|*/AN/PD; Dental Pulp|*EN; Uterus|*EN

MeSH Heading

Amino Acids|AN; Animal; Carbohydrates|AN; Cattle; Chemistry; Chlorides|PD; Chromatography; Dithiothreitol|PD; Electrophoresis, Polyacrylamide Gel; Endonucleases|ME; Female; Glucagon|ME; Insulin|ME; Iron|PD; Molecular Weight; Peptide Fragments|AN/ME; Ribonucleases|ME; Support, U.S. Gov't, P.H.S.; Swine

Publication Type

JOURNAL ARTICLE

ISSN

0022-0345

Country of Publication

UNITED STATES

Record 9 from database: MEDLINE
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Title

SPI-1-dependent host range of rabbitpox virus and complex formation with cathepsin G is associated with serpin motifs.

Author

Moon KB; Turner PC; Moyer RW

Address

Department of Molecular Genetics, University of Florida, Gainesville, Florida 32610-0266, USA.

Source

J Virol, 1999 Nov, 73:11, 8999-9010

Abstract

Serpins are a superfamily of serine proteinase inhibitors which function to regulate a number of key biological processes including fibrinolysis, inflammation, and cell migration. Poxviruses are the only viruses known to encode functional serpins. While some poxvirus serpins regulate inflammation (myxoma virus SERP1 and cowpox virus [CPV] crmA/SPI-2) or apoptosis (myxoma virus SERP2 and CPV crmA/SPI-2), the function of other poxvirus serpins remains unknown. The rabbitpox virus (RPV) SPI-1 protein is 47% identical to crmA and shares all of the serpin structural motifs. However, no serpin-like activity has been demonstrated for SPI-1 to date. Earlier we showed that RPV with the SPI-1 gene deleted, unlike wild-type virus, fails to grow on A549 or PK15 cells (A. Ali, P. C. Turner, M. A. Brooks, and R. W. Moyer, Virology 202:306-314, 1994). Here we demonstrate that in the absence of a functional SPI-1 protein, infected nonpermissive cells which exhibit the morphological features of apoptosis fail to activate terminal caspases or cleave the death substrates PARP or lamin A. We show that SPI-1 forms a stable complex in vitro with cathepsin G, a member of the chymotrypsin family of serine proteinases, consistent with serpin activity. SPI-1 reactive-site loop (RSL) mutations of the critical P1 and P14 residues abolish this activity. Viruses containing the SPI-1 RSL P1 or P14 mutations also fail to grow on A549 or PK15 cells. These results suggest that the full virus host range depends on the serpin activity of SPI-1 and that in restrictive cells SPI-1 inhibits a proteinase with chymotrypsin-like activity and may function to inhibit a caspase-independent pathway of apoptosis.

Language of Publication

English

Unique Identifier

99445805

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MeSH Heading (Major)

Cathepsins|*ME; Peptides|CH/GE/*ME; Serine Proteinase Inhibitors|CH/GE/*ME; Serpins|CH/GE/*ME; Vaccinia Virus|GD/GE/*ME/*PY

MeSH Heading

Amino Acid Motifs; Amino Acid Sequence; Caspases|ME; Cell Line; Chymotrypsin|AI/ME; Human; Molecular Sequence Data; Mutagenesis, Site-Directed; Serine Endopeptidases|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0022-538X

Country of Publication

UNITED STATES

Record 10 from database: MEDLINE
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Title

SPI-1-dependent host range of rabbitpox virus and complex formation with cathepsin G is associated with serpin motifs.

Author

Moon KB; Turner PC; Moyer RW

Address

Department of Molecular Genetics, University of Florida, Gainesville, Florida 32610-0266, USA.

Source

J Virol, 1999 Nov, 73:11, 8999-9010

Abstract

Serpins are a superfamily of serine proteinase inhibitors which function to regulate a number of key biological processes including fibrinolysis, inflammation, and cell migration. Poxviruses are the only viruses known to encode functional serpins. While some poxvirus serpins regulate inflammation (myxoma virus SERP1 and cowpox virus [CPV] crmA/SPI-2) or apoptosis (myxoma virus SERP2 and CPV crmA/SPI-2), the function of other poxvirus serpins remains unknown. The rabbitpox virus (RPV) SPI-1 protein is 47% identical to crmA and shares all of the serpin structural motifs. However, no serpin-like activity has been demonstrated for SPI-1 to date. Earlier we showed that RPV with the SPI-1 gene deleted, unlike wild-type virus, fails to grow on A549 or PK15 cells (A. Ali, P. C. Turner, M. A. Brooks, and R. W. Moyer, Virology 202:306-314, 1994). Here we demonstrate that in the absence of a functional SPI-1 protein, infected nonpermissive cells which exhibit the morphological features of apoptosis fail to activate terminal caspases or cleave the death substrates PARP or lamin A. We show that SPI-1 forms a stable complex in vitro with cathepsin G, a member of the chymotrypsin family of serine proteinases, consistent with serpin activity. SPI-1 reactive-site loop (RSL) mutations of the critical P1 and P14 residues abolish this activity. Viruses containing the SPI-1 RSL P1 or P14 mutations also fail to grow on A549 or PK15 cells. These results suggest that the full virus host range depends on the serpin activity of SPI-1 and that in restrictive cells SPI-1 inhibits a proteinase with chymotrypsin-like activity and may function to inhibit a caspase-independent pathway of apoptosis.

Language of Publication

English

Unique Identifier

99445805

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MeSH Heading (Major)

Cathepsins|*ME; Peptides|CH/GE/*ME; Serine Proteinase Inhibitors|CH/GE/*ME; Serpins|CH/GE/*ME; Vaccinia Virus|GD/GE/*ME/*PY

MeSH Heading

Amino Acid Motifs; Amino Acid Sequence; Caspases|ME; Cell Line; Chymotrypsin|AI/ME; Human; Molecular Sequence Data; Mutagenesis, Site-Directed; Serine Endopeptidases|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0022-538X

Country of Publication

UNITED STATES

Record 11 from database: MEDLINE
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Title

Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function.

Author

Galjart NJ; Morreau H; Willemsen R; Gillemans N; Bonten EJ; dAzzo A

Address

Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.

Source

J Biol Chem, 1991 Aug, 266:22, 14754-62

Abstract

The protective protein was first discovered because of its deficiency in the metabolic storage disorder galactosialidosis. It associates with lysosomal beta-galactosidase and neuraminidase, toward which it exerts a protective function necessary for their stability and activity. Human and mouse protective proteins are homologous to yeast and plant serine carboxypeptidases. Here, we provide evidence that this protein has enzymatic activity similar to that of lysosomal cathepsin A: 1) overexpression of human and mouse protective proteins in COS-1 cells induces a 3-4-fold increase of cathepsin A-like activity; 2) this activity is reduced to approximately 1% in three galactosialidosis patients with different clinical phenotypes; 3) monospecific antibodies raised against human protective protein precipitate virtually all cathepsin A-like activity in normal human fibroblast extracts. Mutagenesis of the serine and histidine active site residues abolishes the enzymatic activity of the respective mutant protective proteins. These mutants, however, behave as the wild-type protein with regard to intracellular routing, processing, and secretion. In contrast, modification of the very conserved Cys60 residue interferes with the correct folding of the precursor polypeptide and, hence, its intracellular transport and processing. The secreted active site mutant precursors, endocytosed by galactosialidosis fibroblasts, restore beta-galactosidase and neuraminidase activities as effectively as wild-type protective protein. These findings indicate that the catalytic activity and protective function of the protective protein are distinct.

Language of Publication

English

Unique Identifier

91317848

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MeSH Heading (Major)

beta-Galactosidase|*ME; Carboxypeptidases|*ME; Cathepsins|*ME; Glycoproteins|*ME; Lysosomes|EN/*ME

MeSH Heading

Amino Acid Sequence; Animal; Cell Line; Chickens; Fluorescent Antibody Technique; Human; Immunohistochemistry; Mice; Microscopy, Immunoelectron; Molecular Sequence Data; Mutagenesis, Site-Directed; Neuraminidase|ME; Sequence Alignment; Transfection

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 12 from database: MEDLINE
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Title

Expression of rat cathepsin D cDNA in Saccharomyces cerevisiae: implications for intracellular targeting of cathepsin D to vacuoles.

Author

Nishimura Y; Takeshima H; Sakaguchi M; Mihara K; Omura T; Kato K; Himeno M

Address

Division of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka.

Source

J Biochem (Tokyo), 1995 Jul, 118:1, 168-77

Abstract

To investigate the intracellular transport mechanisms of lysosomal cathepsin D in yeast cells, we produced cathepsin D in Saccharomyces cerevisiae by placing the coding region under the control of the promoter of the yeast glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Immunoblotting analysis by the use of an antibody specific for rat cathepsin D coding sequence produced an intermediate species which had a slightly higher molecular weight than that of the mature cathepsin D. Cell fractionation experiments demonstrated that the cathepsin D polypeptide was colocalized to the yeast vacuoles with the marker enzyme carboxypeptidase Y in a Ficoll step gradient. A biosynthesis study with pulse-chase kinetic analysis revealed that the precursor polypeptide was accurately sorted to the yeast vacuoles as determined by cell fractionation, and that N-linked carbohydrate modifications were not required for vacuolar sorting of this protein. To elucidate the role of the propeptide region of cathepsin D, which might function in the intracellular targeting to the vacuole, a deletion mutant of cathepsin D lacking the propeptide was prepared and its intracellular targeting was examined after transfection into yeast cells. Immunoblotting analysis demonstrated that the propeptide-deleted mutant protein was recovered in a low quantity as compared with that in the case of yeast cells expressing the wild-type protein in the isolated vacuolar fraction. Immunofluorescence analysis revealed that the deletion mutant protein appeared to be accumulated within the intracellular small vesicles but not in the carboxypeptidase Y-positive vacuoles. Overall, these results indicate that the rat cathepsin D precursor polypeptide is recognized by mechanisms similar to those involved in the intracellular sorting of vacuolar proteins through the ER/Golgi/vacuolar sorting pathway in yeast cells, and that the propeptide has an important function in translocation of the cathepsin D polypeptide to the vacuole.

Language of Publication

English

Unique Identifier

96015165

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MeSH Heading (Major)

Cathepsin D|BI/*GE; DNA, Complementary|*BI; Promoter Regions (Genetics)|*; Vacuoles|*DE/GE

MeSH Heading

Animal; Biological Transport; Fluorescent Antibody Technique, Indirect; Gene Deletion; Glycosylation; Mutation; Rats; Recombinant Proteins|BI; Saccharomyces cerevisiae; Support, Non-U.S. Gov't; Tunicamycin|PD

Publication Type

JOURNAL ARTICLE

ISSN

0021-924X

Country of Publication

JAPAN

Record 13 from database: MEDLINE
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Title

The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation.

Author

Afonso S; Romagnano L; Babiarz B

Address

Department of Cell, Developmental and Neurobiology, Nelson Labs, Busch Campus, Rutgers University, Piscataway, NJ 08855, USA. afonso@rci.rutgers.edu

Source

Development, 1997 Sep, 124:17, 3415-25

Abstract

The implantation of the mouse embryo requires the controlled invasion of the uterine stroma by the embryonic trophoblast. This event is dependent, in part, on the secretion of matrix metalloproteinases and serine proteinases for the extracellular degradation of the uterine matrix. Proteinase activity is controlled by stromal decidualization and specific proteinase inhibitors. This work adds to our understanding of implantation and placentation by reporting the expression and function of another class of proteinases/inhibitors closely related to invasive cell behavior. We focused on the cysteine proteinases, cathepsins B and L, and their inhibitor cystatin C. Northern blots showed that trophoblast expressed cathepsin B throughout the invasive period (days 5.5-10.5). Both cathepsin B message and cathepsin L protein were localized to the mature, invasive trophoblast giant cells. Substrate gel electrophoresis showed an increase in giant cell cathepsin activity with enzyme profiles changing at the end of the invasive period. Northern and western blotting showed that cystatin C, the main inhibitor of cathepsins, was a major product of the decidualizing stroma. Message levels first increased in peripheral decidualizing cells, with the protein localizing close to the embryo during implantation (days 5.5-8.5). With the regression of the decidua beginning on day 9.5, a coordinated upregulation of both cathepsin B and cystatin C was observed implying a role for controlled cathepsin expression during apoptosis. E-64, a synthetic inhibitor of cathepsins B and L, was injected into pregnant females at the stage of blastocyst attachment (days 4.5-5.5). High doses resulted in the complete failure of implantation while lower doses resulted in stunted embryos and a reduced decidual reaction. These results suggested that cathepsins B and L are necessary for normal embryo development and uterine decidualization, and that decidua contributes to their control by a coordinated expression of cystatin C within the implantation site.

Language of Publication

English

Unique Identifier

97454261

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MeSH Heading (Major)

Cathepsin B|AI/*GE/*PH; Cathepsins|AI/*GE/*PH; Cystatins|*GE/*PH; Ovum Implantation|DE/*GE/*PH; Placentation|DE/*GE/*PH

MeSH Heading

Animal; Cysteine Proteinase Inhibitors|PD; Decidua|ME; Female; Gene Expression; In Situ Hybridization; Leucine|AA/PD; Male; Mice; Pregnancy; RNA, Messenger|GE/ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Trophoblast|ME

Publication Type

JOURNAL ARTICLE

ISSN

0950-1991

Country of Publication

ENGLAND

Record 14 from database: MEDLINE
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Title

Comparative effects of cathepsin inhibitors on rat embryonic development in vitro. Evidence that cathepsin D is unimportant in the proteolytic function of yolk sac.

Author

Freeman SJ; Brown NA

Address

 

Source

J Embryol Exp Morphol, 1985 Apr, 86:, 271-81

Abstract

The effects of two proteinase inhibitors, leupeptin and pepstatin on the development of 9.5-day rat conceptuses in vitro has been studied. All cultures were of 48 h duration and the inhibitors were present throughout the entire period. When pepstatin was added to the culture medium (5-25 micrograms/ml) conceptuses developed and grew to an extent that did not differ from untreated controls. However, leupeptin (1-4 micrograms/ml) caused severe growth retardation and abnormal development of conceptuses. The effects of the two inhibitors on the hydrolysis of 125I-labelled BSA and haemoglobin by homogenates of 10.5-day yolk sac indicated the biochemical basis for the differential toxic effects of the two inhibitors on development. Leupeptin was highly inhibitory of the degration of both substrates whereas pepstatin caused no inhibition of 125I-labelled BSA hydrolysis, and only a slight inhibition of haemoglobin hydrolysis. These observations demonstrate that cathepsin D, a lysosomal aspartic proteinase that is specifically inhibited by pepstatin is not involved in yolk-sac-mediated protein utilization by early organogenesis-phase conceptuses and that lysosomal cysteine proteinases, specifically inhibited by leupeptin, are of paramount importance in this yolk sac function.

Language of Publication

English

Unique Identifier

85291486

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MeSH Heading (Major)

Cathepsins|*AI; Fetal Development|*DE; Yolk Sac|*ME

MeSH Heading

Animal; Cathepsin D|ME; Cells, Cultured; Comparative Study; Hemoglobins|ME; Hydrogen-Ion Concentration; Leupeptins|PD; Pepstatins|PD; Rats; Rats, Inbred Strains; Serum Albumin, Bovine|ME; Time Factors

Publication Type

JOURNAL ARTICLE

ISSN

0022-0752

Country of Publication

ENGLAND

Record 15 from database: MEDLINE
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Title

Immunocytochemical studies of cathepsin D in human skeletal muscle.

Author

Whitaker JN; Bertorini TE; Mendell JR

Address

 

Source

Ann Neurol, 1983 Feb, 13:2, 133-42

Abstract

The distribution of cathepsin D, an acidic endopeptidase, was localized by immunocytochemistry in human skeletal muscle obtained from 34 persons with a variety of neuromuscular disorders. Normal human skeletal muscle contained small amounts of cathepsin D, all of which was found close to the sarcolemmal membrane. Immunoreactive cathepsin D was present in the cytoplasm of many infiltrating phagocytic cells and was increased in skeletal muscle fibers from patients with muscular dystrophies, inflammatory myopathies, rhabdomyolysis, acid maltase deficiency, and neurogenic atrophy. In cases of Duchenne type muscular dystrophy, the increase in cathepsin D was especially prominent in small regenerating fibers, in which it was visualized at the ultrastructural level in lysosome-like organelles and extralysosomal locations. The function of cathepsin D in skeletal muscle is unclear, but the present findings suggest a possible role in muscle regeneration and repair. Such a role would necessitate careful selection of drugs which interfere with proteolytic activity if they are to be used as therapeutic agents in treating neuromuscular diseases.

Language of Publication

English

Unique Identifier

83151354

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MeSH Heading (Major)

Cathepsins|*IM; Immunologic Techniques|*; Muscles|*AN/UL

MeSH Heading

Adolescence; Antibodies|AN; Child; Histocytochemistry; Human; Male; Muscular Diseases|ME/PA; Muscular Dystrophies|ME; Neuromuscular Diseases|ME; Support, U.S. Gov't, Non-P.H.S.; Tissue Distribution

Publication Type

JOURNAL ARTICLE

Country of Publication

UNITED STATES

Record 16 from database: MEDLINE
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Title

Changes in sciatic nerve cathepsin D after ligation or exposure to neurotoxins.

Author

Whitaker JN; Dodd SP; Sahenk Z; Mendell JR

Address

 

Source

J Neuropathol Exp Neurol, 1983 Jan, 42:1, 87-98

Abstract

The content and distribution of cathepsin D, a lysosomal acidic endopeptidase, were determined by immunochemical methods in rat sciatic nerve near the site of a ligature or after exposure of animals to neurotoxins. In normal sciatic nerve, cathepsin D was localized predominantly in the perinuclear regions of Schwann cells. In ligated nerve, cathepsin D increased equally in both the proximal and distal nerve segments adjacent to the ligature. Although orthograde and retrograde axonal transport of cathepsin D may have contributed to this increase, immunocytochemical methods indicated that Schwann cells or other phagocytic cells accounted for the bulk of the increased cathepsin D content of nerve. Axonal function was nontraumatically altered by the administration of 2,5-hexanedione, acrylamide, B,B'-iminodipropionitrile or zinc pyridinethione. Exposure to any of these neurotoxins raised cathepsin D content throughout the sciatic nerve twofold or more, and greater amounts of immunoreactive cathepsin D in the cytoplasm of Schwann cells could be demonstrated immunocytochemically. These results indicate that changes in cathepsin D content of Schwann cells may be a reflection of their catabolic activity. The increased Schwann cell cathepsin D content in toxic axonopathies is further proof for an enhanced Schwann cell role as a phagocyte resulting from axonal injury.

Language of Publication

English

Unique Identifier

83111068

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MeSH Heading (Major)

Cathepsins|*AN/PH; Sciatic Nerve|*AN/DE/PH/UL

MeSH Heading

Animal; Axonal Transport|DE; Ligation; Male; Neurotoxins|PD; Rats; Rats, Inbred Strains; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0022-3069

Country of Publication

UNITED STATES

Record 17 from database: MEDLINE
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Title

Effects of cathepsin G pretreatment of platelets on their subsequent responses to aggregating agents.

Author

Kinlough Rathbone RL; Perry DW; Rand ML; Packham MA

Address

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Source

Thromb Res, 1999 Sep, 95:6, 315-23

Abstract

Cathepsin G, a proteolytic enzyme from activated leukocytes, can interact with platelets during inflammation and thrombosis. Platelets that have been exposed to cathepsin G in thrombi may recirculate if they are freed during fibrinolysis. To determine whether some of the subsequent functions of such platelets would be impaired, we investigated the responses of cathepsin G-pretreated platelets to agonists that they would encounter in the circulation. Suspensions of washed human platelets were labeled with [14C]serotonin and resuspended in Tyrode-albumin solution (with 2 mM Ca2+ and apyrase). After 15 minute incubation with 400 nM cathepsin G at 37 degrees C, 52+/-3% of [14C]serotonin had been released, and glycoprotein Ib was degraded. The platelets were washed and resuspended in fresh medium to remove cathepsin G and released materials. Ristocetin-induced agglutination was abolished, indicating that the binding site for von Willebrand Factor on glycoprotein Ib had been removed. Aggregation and release of residual [14C]serotonin in response to 0.1-1.0 U/mL thrombin was blocked or greatly reduced by the cathepsin G pretreatment. This inhibition is probably largely due to cleavage by cathepsin G of some of the protease-activated receptors at the C-terminal side of Ser42 so that the tethered ligand is lost. Pretreatment with cathepsin G did not affect responses to ADP or a low concentration of platelet-activating factor in the presence of fibrinogen, indicating that receptors for these agonists were unaffected and that the function of the fibrinogen receptor, GPIIb/IIIa was unchanged. Responses to cathepsin G, the thrombin receptor-activating peptide SFLLRN, collagen, or the thromboxane A2 mimetic U46619 were partially inhibited, even in the presence of added fibrinogen. Platelet adhesion to a collagen-coated surface was 51+/-7% inhibited, which may indicate cleavage of a collagen receptor or receptors; this may partly account for strong inhibition of collagen-induced aggregation and release of granule contents; additionally, as shown by inhibition of responses to U46619, the function of the thromboxane A2 receptor may be compromised. Thus, although cathepsin G activates platelets, if they recirculate after interaction with it, their subsequent adhesion to damaged vessel walls, aggregation, and release of granule contents induced by thrombin and collagen will be diminished.

Language of Publication

English

Unique Identifier

99454533

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MeSH Heading (Major)

Antibiotics, Peptide|*PD; Cathepsins|*PD; Platelet Aggregation|*DE; Ristocetin|*PD

MeSH Heading

Adenosine Diphosphate|PD; Blood Platelets|ME/PA; Drug Interactions; Hemostatics|PD; Human; Platelet Activating Factor|PD; Platelet Glycoprotein GPIb-IX Complex|ME; Serotonin|ME; Support, Non-U.S. Gov't; Thrombin|PD; Vasoconstrictor Agents|PD; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid|PD

Publication Type

JOURNAL ARTICLE

ISSN

0049-3848

Country of Publication

UNITED STATES

Record 18 from database: MEDLINE
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Title

Effects of cathepsin G pretreatment of platelets on their subsequent responses to aggregating agents.

Author

Kinlough Rathbone RL; Perry DW; Rand ML; Packham MA

Address

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Source

Thromb Res, 1999 Sep, 95:6, 315-23

Abstract

Cathepsin G, a proteolytic enzyme from activated leukocytes, can interact with platelets during inflammation and thrombosis. Platelets that have been exposed to cathepsin G in thrombi may recirculate if they are freed during fibrinolysis. To determine whether some of the subsequent functions of such platelets would be impaired, we investigated the responses of cathepsin G-pretreated platelets to agonists that they would encounter in the circulation. Suspensions of washed human platelets were labeled with [14C]serotonin and resuspended in Tyrode-albumin solution (with 2 mM Ca2+ and apyrase). After 15 minute incubation with 400 nM cathepsin G at 37 degrees C, 52+/-3% of [14C]serotonin had been released, and glycoprotein Ib was degraded. The platelets were washed and resuspended in fresh medium to remove cathepsin G and released materials. Ristocetin-induced agglutination was abolished, indicating that the binding site for von Willebrand Factor on glycoprotein Ib had been removed. Aggregation and release of residual [14C]serotonin in response to 0.1-1.0 U/mL thrombin was blocked or greatly reduced by the cathepsin G pretreatment. This inhibition is probably largely due to cleavage by cathepsin G of some of the protease-activated receptors at the C-terminal side of Ser42 so that the tethered ligand is lost. Pretreatment with cathepsin G did not affect responses to ADP or a low concentration of platelet-activating factor in the presence of fibrinogen, indicating that receptors for these agonists were unaffected and that the function of the fibrinogen receptor, GPIIb/IIIa was unchanged. Responses to cathepsin G, the thrombin receptor-activating peptide SFLLRN, collagen, or the thromboxane A2 mimetic U46619 were partially inhibited, even in the presence of added fibrinogen. Platelet adhesion to a collagen-coated surface was 51+/-7% inhibited, which may indicate cleavage of a collagen receptor or receptors; this may partly account for strong inhibition of collagen-induced aggregation and release of granule contents; additionally, as shown by inhibition of responses to U46619, the function of the thromboxane A2 receptor may be compromised. Thus, although cathepsin G activates platelets, if they recirculate after interaction with it, their subsequent adhesion to damaged vessel walls, aggregation, and release of granule contents induced by thrombin and collagen will be diminished.

Language of Publication

English

Unique Identifier

99454533

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MeSH Heading (Major)

Antibiotics, Peptide|*PD; Cathepsins|*PD; Platelet Aggregation|*DE; Ristocetin|*PD

MeSH Heading

Adenosine Diphosphate|PD; Blood Platelets|ME/PA; Drug Interactions; Hemostatics|PD; Human; Platelet Activating Factor|PD; Platelet Glycoprotein GPIb-IX Complex|ME; Serotonin|ME; Support, Non-U.S. Gov't; Thrombin|PD; Vasoconstrictor Agents|PD; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid|PD

Publication Type

JOURNAL ARTICLE

ISSN

0049-3848

Country of Publication

UNITED STATES

Record 19 from database: MEDLINE
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Title

Effects of cell density and cell proliferation on acid cholesterol esterase and cathepsin activity of cultured human skin fibroblasts.

Author

Kenagy RD; Bierman EL

Address

 

Source

Biochim Biophys Acta, 1983 Nov, 754:2, 174-80

Abstract

We tested the effects of fibroblast cell density and proliferation on the activities of acid cholesterol esterase and cathepsins, the lysosomal enzymes which degrade low-density lipoprotein. Rates of cell proliferation were increased by: (1) fibroblast conditioned medium, (2) increasing the time since subculture from 3 to 7 days, and (3) decreasing the plating density of cells. Cathepsin activity was consistently decreased as cellular proliferation was increased by these various methods. Changes in acid cholesterol esterase activity were more variable. For example, acid cholesterol esterase activity was consistently a positive function of cell density only at densities under 3 micrograms protein/cm2, while cathepsin activity increased up to densities of 16 micrograms protein/cm2. However, the activities of both enzymes were lower at cell densities of under 3 micrograms cell protein/cm2 compared to confluent cultures. Sparse fibroblast cultures may provide a unique model system to study low-density lipoprotein metabolism since, at low cell density, LDL receptor activity is high while lysosomal activity is low, making it possible that lysosomal degradation could become the rate-limiting step in the process of LDL degradation rather than receptor-mediated internalization of the lipoprotein. This might then allow an accumulation of lipoprotein-derived cholesteryl esters in the cell. Such a model could be relevant to the propensity of arterial cells to become foam cells during atherogenesis.

Language of Publication

English

Unique Identifier

84080495

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MeSH Heading (Major)

Carboxylic Ester Hydrolases|*ME; Cathepsins|*ME; Cholesterol Esterase|*ME; Receptors, Cell Surface|*PD; Skin|*EN

MeSH Heading

Cell Count; Cell Division; Cells, Cultured; Fibroblasts|EN; Human; Hydrogen-Ion Concentration; Lipoproteins, LDL|ME; Lysosomes|EN; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-3002

Country of Publication

NETHERLANDS

Record 20 from database: MEDLINE
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Title

Identification and characterization of the Cydia pomonella granulovirus cathepsin and chitinase genes.

Author

Kang W; Tristem M; Maeda S; Crook NE; OReilly DR

Address

Department of Biology, Imperial College of Science, Technology and Medicine, London, UK.

Source

J Gen Virol, 1998 Sep, 79 ( Pt 9):, 2283-92

Abstract

A 3.2 kb BamHI-EcoRI fragment of the Cydia pomonella granulovirus (CpGV) genome was subcloned and characterized. Sequence analysis revealed two complete and one partial open reading frames (ORFs). ORF7L is predicted to encode a 66.7 kDa protein (594 amino acid residues) that is 57% identical (amino acid sequence) to the chiA gene (ORF126) of Autographa californica nucleopolyhedrovirus (AcMNPV), encoding a chitinase. ORF8R is 333 amino acids in length and shows high similarity (between 64% and 67%) with baculovirus cathepsins. The partial ORF, ORF5L, is related to AcMNPV ORF145 of unknown function. Phylogenetic trees were constructed for both chitinase and cathepsin sequences from baculoviruses and other species. In both cases, the baculovirus sequences were monophyletic but with a deep division between the GVs and NPVs, suggesting both genes were present in an ancestral virus prior to the separation of the two genera. However, these studies did not provide definitive evidence for the origin of either protein in baculoviruses. To investigate CpGV cathepsin function, a rescue experiment was performed using a Bombyx mori NPV (BmNPV) mutant (BmCysPD) which lacks a functional cathepsin (cath) gene. Larvae infected with BmCysPD-Cp.cat, a BmCysPD derivative carrying CpGV cath, showed similar symptoms to wild-type BmNPV infected insects, confirming that CpGV cath encodes a functional cathepsin. Primer extension analysis of mRNA from BmCysPD-Cp.cat infected cells showed that CpGV cath transcription was initiated from a consensus late transcription motif (ATAAG) within the CpGV sequences, indicating that a CpGV late promoter motif was recognized in this NPV system.

Language of Publication

English

Unique Identifier

98418511

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MeSH Heading (Major)

Baculoviridae|*EN/*GE/PY; Cathepsins|*GE; Chitinase|*GE; Genes, Viral|*; Moths|*VI

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Cell Line; Cysteine Endopeptidases|GE; DNA, Viral|GE; Larva|VI; Molecular Sequence Data; Open Reading Frames; Phylogeny; Recombination, Genetic; Restriction Mapping; Sequence Homology, Amino Acid; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0022-1317

Country of Publication

ENGLAND

Record 21 from database: MEDLINE
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Title

Effects of human neutrophil elastase and cathepsin G on the reactivity of platelets with antiplatelet antibodies.

Author

Bykowska K; Maslanka K; Uhrynowska M; Kopec M; Lopaciuk S

Address

Laboratory or Blood Coagulation and Hemostasis, Institute of Hematology and Blood Transfusion, Warsaw.

Source

Acta Haematol Pol, 1995, 26:2, 163-70

Abstract

Two human neutrophil serine proteases, elastase (HNE) and cathepsin G (CathG), are known to change the structure and hemostatic function of platelet surface membrane. The platelet membrane contains glycoproteins (GPs) which function as alloantigens, autoantigens and targets of drug-induced antibodies. The aim of this study was to investigate whether proteolysis of platelet GPs by HNE and CathG is associated with changes in the reactivity of platelets to antiplatelet antibodies. The platelet immunoreactivity was examined using the MAIPA (monoclonal antibody-specific immobilization of platelet antigens) assay and PSIFT (platelet suspension immunofluorescence test). The treatment of platelets with HNE led to a moderate increase in their reactivity to quinidine-dependent (anti-GP Ib) antibody and to a slight decline in the expression of HPA-1a. In contrast, CathG did not provoke any significant changes in platelet reactions with quinidine dependent and anti-HPA-1a antibodies. Both enzymes had no significant effect on the expression of HLA-A2, HLA-A3, HLA-B7 and HLA-B8 on platelets.

Language of Publication

English

Unique Identifier

95381743

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MeSH Heading (Major)

Antibodies|*IM; Blood Platelets|*IM; Cathepsins|*ME; Pancreatopeptidase|*ME; Platelet Membrane Glycoproteins|*ME; Serine Proteinases|*ME

MeSH Heading

Fluorescent Antibody Technique; Human; Immunoblotting; In Vitro

Publication Type

JOURNAL ARTICLE

ISSN

0001-5814

Country of Publication

POLAND

Record 22 from database: MEDLINE
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Title

The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis.

Author

Rudenko G; Bonten E; Hol WG; dAzzo A

Address

Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle 98195-7742, USA.

Source

Proc Natl Acad Sci U S A, 1998 Jan, 95:2, 621-5

Abstract

Human protective protein/cathepsin A (PPCA), a serine carboxypeptidase, forms a multienzyme complex with beta-galactosidase and neuraminidase and is required for the intralysosomal activity and stability of these two glycosidases. Genetic lesions in PPCA lead to a deficiency of beta-galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis. Eleven amino acid substitutions identified in mutant PPCAs from clinically different galactosialidosis patients have now been modeled in the three-dimensional structure of the wild-type enzyme. Of these substitutions, 9 are located in positions likely to alter drastically the folding and stability of the variant protein. In contrast, the other 2 mutations that are associated with a more moderate clinical outcome and are characterized by residual mature protein appeared to have a milder effect on protein structure. Remarkably, none of the mutations occurred in the active site or at the protein surface, which would have disrupted the catalytic activity or protective function. Instead, analysis of the 11 mutations revealed a substantive correlation between the effect of the amino acid substitution on the integrity of protein structure and the general severity of the clinical phenotype. The high incidence of PPCA folding mutants in galactosialidosis reflects the fact that a single point mutation is unlikely to affect both the beta-galactosidase and the neuraminidase binding sites of PPCA at the same time to produce the double glycosidase deficiency. Mutations in PPCA that result in defective folding, however, disrupt every function of PPCA simultaneously.

Language of Publication

English

Unique Identifier

98118562

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MeSH Heading (Major)

Carboxypeptidases|*CH/GE/ME; Lysosomal Storage Diseases|GE/*ME; Models, Molecular|*

MeSH Heading

Human; Mutation; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0027-8424

Country of Publication

UNITED STATES

Record 23 from database: MEDLINE
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Title

Localization of cathepsin B in normal and hyperplastic human prostate by immunoperoxidase and protein A-gold techniques.

Author

Sinha AA; Gleason DF; Limas C; Reddy PK; Wick MR; Hagen KA; Wilson MJ

Address

Veterans Administration Medical Center Research Service, Minneapolis, Minnesota 55417.

Source

Anat Rec, 1989 Mar, 223:3, 266-75

Abstract

Cathepsin B, a lysosomal cysteine protease, was localized in normal prostate and benign prostatic hyperplasia (BPH) using immunoperoxidase and protein A-gold techniques. Our objective was to determine whether cathepsin B was involved in the prostatic epithelium affected by nodular hyperplasia. All samples were collected immediately after prostatectomy. Immunohistochemical studies showed that the enzyme was expressed in the supranuclear cytoplasm of columnar cells and in numerous basal cells of normal and BPH acini. The strongest localization of cathepsin B occurred in acinar basal cells; hence, it is possible that cathepsin B could be useful as a marker for such cellular elements. Stromal macrophages showed reaction products, but lymphocytes and neutrophils did not. In both normal and hyperplastic glands, the enzyme was localized by gold particles in lysosomes, secretory granules, and vacuoles of columnar epithelial acinar cells. Immunoelectron microscopic study also showed the presence of cathepsin B in the heterochromatin (condensed chromatin) and nuclear membranes of columnar and basal cells, but not in euchromatin or nucleoli. At present, the function of cathepsin B in the nuclei of basal and columnar cells remains unknown. However, the cathepsin B in the cytoplasmic compartment might be associated with the lysosomal function of the cells. The role of cathepsin B as a marker for basal cell participation in the development of prostatic lesions should be studied further.

Language of Publication

English

Unique Identifier

89164840

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MeSH Heading (Major)

Cathepsin B|IM/*ME; Prostate|*ME/PA

MeSH Heading

Gold|DU; Human; Hyperplasia; Immune Sera|IM; Immunoenzyme Techniques; Male; Reference Values; Staphylococcal Protein A|DU; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Tissue Distribution

Publication Type

JOURNAL ARTICLE

ISSN

0003-276X

Country of Publication

UNITED STATES

Record 24 from database: MEDLINE
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Title

Progesterone and estrogen control of the response of rat uterine lysosomal cathepsin D activity to a deciduogenic stimulus.

Author

Moulton BC

Address

 

Source

Endocrinology, 1982 Apr, 110:4, 1197-202

Abstract

Endometrial sensitization to deciduogenic stimuli and destruction of luminal epithelial cells during the uterine decidual reaction may depend upon the control of endometrial lysosome function by progesterone and estradiol. These experiments examined progesterone and estrogen control of the levels of uterine cathepsin D and the response of cathepsin D activity to a deciduogenic stimulus. The progestin medroxyprogesterone acetate increased rates of uterine cathepsin D synthesis, but these rates were not enhanced by estradiol pretreatment. The response of cathepsin D activity to a deciduogenic stimulus, however, required progestin pretreatment, followed by estrogen treatment. Decreases in cathepsin D activity after a deciduogenic stimulus required estrogen stimulation for approximately 12 h, and this estrogen effect could be suppressed by treatment with dexamethasone or inhibitors of prostanoid synthesis. These results indicate that destruction of luminal epithelial cells during the uterine decidual reaction involves the coordinated control of the cathepsin D content by progesterone and of intracellular lysosome activity by estradiol.

Language of Publication

English

Unique Identifier

82138551

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MeSH Heading (Major)

Cathepsins|*ME; Decidua|*PH; Estrogens|*PD; Lysosomes|*EN; Progesterone|*PD; Uterus|*EN

MeSH Heading

Animal; Castration; Dexamethasone|PD; Estradiol|PD; Estriol|PD; Female; Meclofenamic Acid|PD; Medroxyprogesterone|AA/PD; Pseudopregnancy|EN; Rats; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0013-7227

Country of Publication

UNITED STATES

Record 25 from database: MEDLINE
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Title

Urine activity of cathepsin B, collagenase and urine excretion of TGF-beta 1 and fibronectin in membranous glomerulonephritis.

Author

Senatorski G; Paczek L; Su…owicz W; Gradowska L; Bart…omiejczyk I

Address

Department of Immunotherapy, Medical University of Warsaw, Poland.

Source

Res Exp Med (Berl), 1998 Dec, 198:4, 199-206

Abstract

In 30% of cases nephrotic syndrome is caused by membranous glomerulonephritis (MG). Protein accumulation in glomeruli leads to progressive loss of kidney function and damage of structure in MG. The role of tissue proteolytic systems and growth factors in this process is not known. The purpose of the study was to estimate urine cathepsin B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG. Cathepsin B activity was greater in the urine of MG patients than in the control group (10.58 +/- 8.73 pmol AMC/mg creatinine per min-1 vs control 7.11 +/- 2.05 pmol AMC/mg creatinine per min-1; P < 0.05). Urine collagenase activity was higher in the group of patients than in the control group (8.59 +/- 4.26 pmol AMC/mg creatinine per min-1 vs control 3.84 +/- 2.09 pmol AMC/mg creatinine per min-1 P < 0.02). Urine excretion of fibronectin (45.60 ng/mg creatinine vs control 10.30 ng/mg creatinine; P < 0.04) and TGF-beta 1 levels in the urine were higher than in controls (283.55 +/- 248.13 pg/ml vs 36.11 +/- 48.01 pg/ml; P < 0.01). Results suggest glomerular overproduction of TGF-beta 1 and urinary leak of proteolytic enzymes (PE). This may result in decreased glomerular PE activity in MG and, with time, may lead to protein accumulation in renal glomeruli and to progressive loss of kidney function and damage of structures as the course of MG progresses. PE urine composition as well as ECM protein and cytokine urine excretion may allow noninvasive glomerulopathy course monitoring in humans in the future.

Language of Publication

English

Unique Identifier

99095671

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MeSH Heading (Major)

Cathepsin B|*UR; Collagenases|*UR; Fibronectins|*UR; Glomerulonephritis, Membranous|*UR; Transforming Growth Factor beta|BL/*UR

MeSH Heading

Adult; Female; Human; Male; Middle Age

Publication Type

JOURNAL ARTICLE

ISSN

0300-9130

Country of Publication

GERMANY

Record 26 from database: MEDLINE
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Title

Structures at the proteolytic processing region of cathepsin D.

Author

Yonezawa S; Takahashi T; Wang XJ; Wong RN; Hartsuck JA; Tang J

Address

Laboratory of Protein Studies, Oklahoma Medical Research Foundation, Oklahoma City.

Source

J Biol Chem, 1988 Nov, 263:31, 16504-11

Abstract

The amino acid sequences at the "proteolytic processing regions" of cathepsin Ds have been determined for the enzymes from cows, pigs, and rats in order to deduce the sites of cleavage as well as the function of the proteolytic processing of cathepsin D. For bovine cathepsin D, the "processing region" sequence was determined from a peptide isolated from the single-chain enzyme. The COOH-terminal sequence of the light chain and the NH2-terminal sequence of the heavy chain were also determined. The processing region sequence of porcine cathepsin D was determined from its cDNA structure, and the same structure from rat cathepsin D was determined from the peptide sequence of the single-chain rat enzyme. From sequence homology to other aspartic proteases whose x-ray crystallographic structures are known, such as pepsinogen and penicillopepsin, it is clear that the processing regions are insertions to form an extended beta-hairpin loop between residues 91 and 92 (porcine pepsin numbers). However, the sizes of the processing regions of cathepsin Ds from different species are considerably different. For the enzymes from rats, cows, pigs, and human, the sizes of the processing regions are 6, 9, 9, and 11 amino acid residues, respectively. The amino acid sequences within the processing regions are considerably different. In addition, the proteolytic processing sites were found to be completely different in the bovine and porcine cathepsin Ds. While in the porcine enzyme, an Asn-Ser bond and a Gly-Val bond are cleaved to release 5 residues as a consequence of the processing; in the bovine enzyme, two Ser-Ser bonds are cleaved to release 2 serine residues. These findings would argue that the in vivo proteolytic processing of the cathepsin D single chain is probably not carried out by a specific "processing protease." Model building of the cathepsin D processing region conformation was conducted utilizing the homology between procathepsin D and porcine pepsinogen. The beta-hairpin structure of the processing region was found to (i) interact with the activation peptide of the procathepsin D in a beta-structure and (ii) place the Cys residue in the processing region within disulfide linkage distance to Cys-27 of cathepsin D light chain. These observations support the view that the processing region of cathepsin D may function to stabilize the conformation of procathepsin D and may play a role in its activation.

Language of Publication

English

Unique Identifier

89034127

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MeSH Heading (Major)

Cathepsin D|*GE; Protein Processing, Post-Translational|*

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Cattle; Comparative Study; Computer Graphics; Human; Models, Molecular; Molecular Sequence Data; Protein Conformation; Rats; Species Specificity; Support, U.S. Gov't, P.H.S.; Swine

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 27 from database: MEDLINE
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Title

Granulocyte-angiotensin system. Identification of angiotensinogen as the plasma protein substrate of leukocyte cathepsin G.

Author

Wintroub BU; Klickstein LB; Dzau VJ; Watt KW

Address

 

Source

Biochemistry, 1984 Jan, 23:2, 227-32

Abstract

Cathepsin G, a human lysosomal neutral protease, converts angiotensin I to angiotensin II and cleaves angiotensin II from a plasma protein substrate. Experiments were designed that identified and characterized cathepsin G substrate as human angiotensinogen. A total of 2, 5, and 10 micrograms of purified substrate, incubated with 2 microL of partially purified human renin (2 Goldblatt units/mg) for 60 min at 37 degrees C, generated 2, 9, and 22 pmol of angiotensin I. Cathepsin G substrate and renin substrate activities copurified during Affi-Gel Blue affinity chromatography, hydroxylapatite chromatography, phenyl-Sepharose chromatography, and S-200 gel filtration. Disc gel electrophoresis of 10 micrograms of purified protein gave a single band containing both activities. The amino-terminal sequence contained the covalent structure of angiotensin I and was Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-X-Glu-Ser-Thr-Cys-Gl u-. Reduced and unreduced angiotensinogens were subjected to sodium dodecyl sulfate gel electrophoresis, and each gel showed two bands of Mr 65 000 and 62 000. The isoelectric point of the Mr 65 000 form was pH 4.5-4.3 and the Mr 62 000 form was pH 4.9. Functional, structural, and physiochemical evidence demonstrates that the substrate of cathepsin G is angiotensinogen. Thus, human neutrophils may utilize angiotensin I or angiotensinogen as substrate for angiotensin II generation. The granulocyte-angiotensin system does not require renin or converting enzyme and may function as a mobile effector pathway which modulates tissue blood flow and/or vascular permeability.

Language of Publication

English

Unique Identifier

84128540

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MeSH Heading (Major)

Angiotensinogen|IP/*ME; Angiotensins|*ME; Cathepsins|*BL/IP; Granulocytes|*EN; Leukocytes|*EN

MeSH Heading

Amino Acids|AN; Human; Kinetics; Lysosomes|EN; Renin-Angiotensin System; Substrate Specificity; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-2960

Country of Publication

UNITED STATES

Record 28 from database: MEDLINE
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Title

Modulation of interferon gamma induced increases in cathepsin B in THP-1 cells by adrenergic agonists and antagonists.

Author

Li Q; Bever CT Jr

Address

Departments of Neurology and Pharmacology and Experimental Therapeutics, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, 21201, USA.

Source

Cell Biol Int, 1998, 22:1, 13-20

Abstract

In order to investigate the possible modulation of macrophage function by the autonomic nervous system, the effect of adrenergic agonists and antagonists on interferon (IFN)-gamma-induced increases in cathepsin B (CB) in a macrophage-like cell line was studied. It has been shown previously that IFN-gamma induces increased CB activity in phorbol myristate acetate (PMA)-primed THP-1 cells. Isoproterenol (ISO) (10 micrometers), a mixed beta-receptor agonist, increased the induction of CB activity in the cells but norepinephrine (10 micrometers) and epinephrine (10 micrometers), the alpha and beta receptor agonists, had little effect. The addition of the mixed alpha-receptor antagonist phentolamine (10 micrometers) had no effect on ISO induced increases but the mixed beta-receptor antagonist propranolol (10 micrometers) and the selective beta1-receptor antagonist atenolol produced significant inhibition. These results suggest that the activation of beta-receptors could be involved in the induction of CB activity in macrophages and provide a possible mechanism for the regulation of macrophage effector function by the autonomic nervous system. Dibutyryl cAMP (1 mm) alone also induced increases in CB in THP-1 cells, and H-89 or HA1004 abrogated the effect of dibutyryl cAMP, suggesting that the effect of ISO on CB could be through the elevation of cAMP and the activation of cAMP-dependent protein kinases. Copyright 1998 Academic Press.

Language of Publication

English

Unique Identifier

99047439

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MeSH Heading (Major)

Adrenergic Agonists|*PD; Adrenergic Antagonists|*PD; Cathepsin B|*ME; Interferon-gamma, Recombinant|*PD

MeSH Heading

Bucladesine|PD; Cell Line; Cyclic AMP-Dependent Protein Kinases|ME; Human; Isoproterenol|PD; Macrophages|DE/EN; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Tetradecanoylphorbol Acetate|PD

Publication Type

JOURNAL ARTICLE

ISSN

1065-6995

Country of Publication

ENGLAND

Record 29 from database: MEDLINE
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Title

Ontogeny, immunocytochemical localization, and biochemical properties of the pregnancy-associated uterine elastase/cathepsin-G protease inhibitor, antileukoproteinase (ALP): monospecific antibodies to a synthetic peptide recognize native ALP.

Author

Simmen RC; Michel FJ; Fliss AE; Smith LC; Fliss MF

Address

Department of Animal Science, University of Florida, Gainesville 32611.

Source

Endocrinology, 1992 Apr, 130:4, 1957-65

Abstract

Expression of the mRNA encoding the elastase/cathepsin-G protease inhibitor, antileukoproteinase (ALP), is highest in pig uterus during mid- and late pregnancy, suggesting a stage of pregnancy-dependent role for ALP in feto-maternal interactions. To elucidate a function for ALP in these events, immunogenic probes were developed to localize sites of ALP expression in the environment of the developing fetus. Monospecific antibodies raised against a 16-mer synthetic peptide corresponding to residues 21-36 (ALP 16P) of the deduced amino acid sequence of pig uterine ALP were generated by active immunization of sheep. ALP 16P conjugated to keyhole limpet hemocyanin elicited high titer antibodies that were specific to ALP. The antipeptide antibodies were used to characterize pig uterine ALP from allantoic fluids. Uterine ALP has an approximate mol wt of 14,000 and a pI of 8.2 and exhibits elastase inhibitor activity. Amino-terminal amino acid sequencing of uterine ALP indicated the sequence AENALKGGACPPRKIVQC, which has 44% identity with the corresponding region in human bronchial ALP. RIA for ALP, developed using ALP 16P as standard and iodinated tracer, demonstrated the presence of immunoreactive ALP in early, mid-, and late pregnant endometrium and myometrium, placenta, allantoic fluids, fetal cord blood, and fetal liver. ALP was undetectable in the maternal circulation. The ALP levels in endometrium, allantoic fluids, and fetal cord blood changed with the stage of pregnancy; however, ALP content in placenta, myometrium, and fetal liver, although different among tissues, remained invariant during gestation. By immunocytochemical analyses, ALP was localized in the glandular epithelium of the uterus, in placenta, and in fetal liver, consistent with the presence of immunoreactive ALP as measured by RIA. The localization of uterine ALP in placenta and its corresponding transport to fetal circulation provide strong evidence to support a physiological function for the protease inhibitor in the biological mechanisms controlling fetal development in utero.

Language of Publication

English

Unique Identifier

92191891

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MeSH Heading (Major)

Antibodies|*IM; Serine Proteinase Inhibitors|*AN/GE/IM

MeSH Heading

Amino Acid Sequence; Animal; Female; Immunohistochemistry; Maternal-Fetal Exchange; Molecular Sequence Data; Pregnancy; RNA, Messenger|AN; Sheep; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; Swine; Uterus|CH

Publication Type

JOURNAL ARTICLE

ISSN

0013-7227

Country of Publication

UNITED STATES

Record 30 from database: MEDLINE
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Title

Histochemical localization of cathepsin B at the invasion front of the rabbit V2 carcinoma.

Author

Graf M; Baici A; Sträuli P

Address

 

Source

Lab Invest, 1981 Dec, 45:6, 587-96

Abstract

To clarify the role of cathepsin B in tumor invasion, the enzyme was visualized in tissue frozen sections of the subcutaneously growing rabbit V2 carcinoma. Localization of cathepsin B was achieved by immunofluorescent staining and by enzyme histochemistry. For the former approach, a sheep antiserum was raised against purified cathepsin B from rabbit liver. The antibodies, isolated by immunoadsorption, reacted monospecifically with rabbit liver cathepsin B in Ouchterlony double diffusion and in immunoelectrophoresis. In the enzyme histochemical assay, Z-Ala-Arg-Arg-methoxynaphtylamide was used as fluorogenic substrate and nitrosalicylaldehyde as coupling agent. With both methods, cathepsin B was found to be localized within fibroblasts and leukocytes assembled at the tumor invasion front. In addition, immunofluorescent staining demonstrated the occurrence of the enzyme in the extracellular matrix surrounding tumor cell clusters. Carcinoma cells always remained unstained. The conclusion is drawn that cathepsin B is chiefly produced by host cells which are stimulated to increase synthesis and to release the enzyme under the influence of the tumor. A dual function can be ascribed to cathepsin B concentrated in the vicinity of the tumor: it operates intracellularly (in host cells) through degradation of endocytosed protein and extracellularly through activation of collagenase. The resulting lytic action on host structures appears to be a prerequisite for local spread of the V2 carcinoma.

Language of Publication

English

Unique Identifier

82102255

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MeSH Heading (Major)

Cathepsins|IM/*IP; Cell Transformation, Neoplastic|*AN/PA; Liver|*AN; Neoplasms, Experimental|*AN/PA

MeSH Heading

Animal; Antibodies; Fluorescent Antibody Technique; Histocytochemistry; Rabbits; Sheep; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0023-6837

Country of Publication

UNITED STATES

Record 31 from database: MEDLINE
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Title

Direct affinity purification and supramolecular organization of human lysosomal cathepsin A.

Author

Pshezhetsky AV; Potier M

Address

Service de GÆenÆetique MÆedicale, HÈopital Sainte-Justine, MontrÆeal, QuÆebec, Canada.

Source

Arch Biochem Biophys, 1994 Aug, 313:1, 64-70

Abstract

Cathepsin A (also named "protective protein" and carboxypeptidase L) stabilizes beta-galactosidase and activates neuraminidase by forming with them a high-molecular-weight lysosomal complex. We determined the main forms of the supramolecular organization of human placental cathepsin A and the quantitative relationship between them, using an affinity chromatography on agarose-Phe-Leu for direct purification of cathepsin A. We found that cathepsin A in human placenta exists as the following three forms: a 1270-kDa complex with beta-galactosidase and neuraminidase (about 1% of total cathepsin A), a 680-kDa complex with beta-galactosidase (30-40% of total), and a free 98-kDa cathepsin A dimer (60-70% of total). All forms are in dynamic equilibrium with each other, but almost all placental beta-galactosidase is associated with cathepsin A in the 680-kDa complex. The main properties of free cathepsin A (including the capacity to associate with beta-galactosidase) were found to be identical to those of cathepsin A obtained by dissociation of the 680-kDa complex. The presence of a free cathepsin A pool in the lysosome is connected with its sixfold overproduction in the cell compared to beta-galactosidase and may be necessary to ensure cathepsin A proteolytic function in addition to its protective role for beta-galactosidase and neuraminidase in the lysosomal multienzymatic complex. Such a dual function of cathepsin A is also confirmed by our finding that it is the only carboxypeptidase of placenta extract able to catalyze the hydrolysis of both carbobenzoxy (CBZ)-Glu-Tyr and CBZ-Phe-Leu dipeptide substrates.

Language of Publication

English

Unique Identifier

94330723

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MeSH Heading (Major)

Carboxypeptidases|*CH; Cathepsins|*CH; Lysosomes|EN/*UL

MeSH Heading

beta-Galactosidase|CH; Amino Acid Sequence; Human; Macromolecular Systems; Molecular Sequence Data; Neuraminidase|CH; Placenta|EN/UL; Protein Binding

Publication Type

JOURNAL ARTICLE

ISSN

0003-9861

Country of Publication

UNITED STATES

Record 32 from database: MEDLINE
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Title

Morphine induces splenocyte apoptosis and enhanced mRNA expression of cathepsin-B.

Author

Singhal PC; Reddy K; Franki N; Sanwal V; Gibbons N

Address

Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.

Source

Inflammation, 1997 Dec, 21:6, 609-17

Abstract

Morphine has been demonstrated to modulate immune function. We studied whether morphine modulates apoptosis of splenocytes. Splenocytes were isolated from control and morphine treated rats. Splenocytes isolated from morphine treated rats showed increased percentage (P < 0.001) of apoptosis when compared to splenocytes isolated from untreated rats (control, 4.7 +/- 1.0% apoptotic splenocytes/field vs. morphine, 47.8 +/- 3.4% apoptotic splenocytes/field). These results were further confirmed by gel electrophoresis as well as by end-labeling DNA of splenocytes isolated from control and morphine treated rats. Splenocytes from morphine treated rats showed a classical ladder pattern with integer multiples of 180 base pairs. Splenocytes from morphine treated rats also showed increased mRNA expression of cathepsin-B, a gene associated with active cell death. These results suggest that morphine may also be modulating immune function by enhancing apoptosis of splenocytes.

Language of Publication

English

Unique Identifier

98091743

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MeSH Heading (Major)

Apoptosis|*DE; Cathepsin B|*BI; Morphine|*PD; Narcotics|*PD; Spleen|ME/*PA

MeSH Heading

Animal; Rats; Rats, Sprague-Dawley; RNA, Messenger|BI; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0360-3997

Country of Publication

UNITED STATES

Record 33 from database: MEDLINE
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Title

The human cathepsin F gene--a fusion product between an ancestral cathepsin and cystatin gene.

Author

Wex T; Wex H; Brömme D

Address

Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Source

Biol Chem, 1999 Dec, 380:12, 1439-42

Abstract

Human cathepsin F is a novel papain-like cysteine protease of unknown function. Here, we describe the complete human cathepsin F (CTSF) gene which is composed of 13 exons. In addition to a previous report, two novel upstream located exons whose splice sites interrupted the propeptide of cathepsin F within the 'cystatin-like' domain, recently described by Nagler et al. (Biochem. Biophys. Res. Comm. 257, 313-318, 1999) were identified. A comparison of the genomic structures between this novel part of the cathepsin F gene and those of several cystatin genes revealed striking similarities, supporting the hypothesis that the cathepsin F gene resulted from a gene fusion between an ancestral cystatin and cathepsin gene.

Language of Publication

English

Unique Identifier

20125514

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MeSH Heading (Major)

Cathepsins|*GE; Cystatins|*GE

MeSH Heading

Amino Acid Sequence; Exons; Human; Introns; Molecular Sequence Data; Recombinant Fusion Proteins|GE; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

1431-6730

Country of Publication

GERMANY

Record 34 from database: MEDLINE
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Title

Adsorption and helical coiling of amphipathic peptides on lipid vesicles leads to negligible protection from cathepsin B or cathepsin D.

Author

Goldschmidt TG; Reyes VE; You G; Nelson DJ; Reisert PS; Anderson J; Mole J; Humphreys RE

Address

Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.

Source

Immunol Invest, 1993 Feb, 22:1, 25-40

Abstract

The processing of antigenic peptides for presentation by MHC molecules to T cells, may depend upon the function of a second, consensus sequence in or near the T cell-presented epitope. One such processing-regulating sequence appears to be composed of amino acids Leu, Ile, Val, Phe, and Met recurring in a fashion to form a longitudinal, hydrophobic strip when the excised peptide is coiled as an alpha-helix. Such a hydrophobic strip-of-helix may: (a) scavenge peptides from lumens onto lipid membranes of digestion vesicles, (b) stabilize peptides there as protease-resistant helices, (c) specify recognition by the antigenic peptide-binding sites of chaperonin proteins, transmembranal transporters, or MHC molecules. By circular dichroism and electron paramagnetic resonance, we demonstrated that peptides with recurrent hydrophobic residues potentially forming longitudinal strips adsorbed to, and partially coiled as helices on, di-O-hexadecyl, D-L-alpha-phosphatidylcholine (DHPC) vesicles. Cathepsin B or cathepsin D cleavages of three such peptides were identified. With either enzyme, it made no significant difference whether a peptide substrate was in solution or bound to vesicles in terms of efficiency and specificity of peptide bond cleavages. We conclude that protease resistance, per se, of membrane-adsorbed, helically coiled peptides is not a major factor in the selection for T cell presentation of epitopes in peptides which have a motif with a longitudinal hydrophobic strip.

Language of Publication

English

Unique Identifier

93179049

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MeSH Heading (Major)

Cathepsin B|*ME; Cathepsin D|*ME; Liposomes|*; Peptide Fragments|*CH/DE; Protein Structure, Secondary|*

MeSH Heading

Adsorption; Amino Acid Sequence; Animal; Antigen-Presenting Cells|ME; Electron Spin Resonance Spectroscopy; Molecular Sequence Data; Phospholipid Ethers; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0882-0139

Country of Publication

UNITED STATES

Record 35 from database: MEDLINE
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Title

Crystal structure of porcine cathepsin H determined at 2.1 A resolution: location of the mini-chain C-terminal carboxyl group defines cathepsin H aminopeptidase function.

Author

Guncar G; Podobnik M; Pungercar J; Strukelj B; Turk V; Turk D

Address

Department of Biochemistry and Molecular Biology, JoÅzef Stefan Institute, Ljubljana, Slovenia. gregor.guncar@ijs.si

Source

Structure, 1998 Jan, 6:1, 51-61

Abstract

BACKGROUND: Cathepsin H is a lysosomal cysteine protease, involved in intracellular protein degradation. It is the only known mono-aminopeptidase in the papain-like family and is reported to be involved in tumor metastasis. The cathepsin H structure was determined in order to investigate the structural basis for its aminopeptidase activity and thus to provide the basis for structure-based design of synthetic inhibitors. RESULTS: The crystal structure of native porcine cathepsin H was determined at 2.1 A resolution. The structure has the typical papain-family fold. The so-called mini-chain, the octapeptide EPQNCSAT, is attached via a disulfide bond to the body of the enzyme and bound in a narrowed active-site cleft, in the substrate-binding direction. The mini-chain fills the region that in related enzymes comprises the non-primed substrate-binding sites from S2 backwards. CONCLUSIONS: The crystal structure of cathepsin H reveals that the mini-chain has a definitive role in substrate recognition and that carbohydrate residues attached to the body of the enzyme are involved in positioning the mini-chain in the active-site cleft. Modeling of a substrate into the active-site cleft suggests that the negatively charged carboxyl group of the C terminus of the mini-chain acts as an anchor for the positively charged N-terminal amino group of a substrate. The observed displacements of the residues within the active-site cleft from their equivalent positions in the papain-like endopeptidases suggest that they form the structural basis for the positioning of both the mini-chain and the substrate, resulting in exopeptidase activity.

Language of Publication

English

Unique Identifier

98154318

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MeSH Heading (Major)

Aminopeptidases|*CH; Cathepsins|*CH; Cysteine Endopeptidases|*CH

MeSH Heading

Amino Acid Sequence; Animal; Binding Sites|PH; Cathepsin B|CH; Crystallography, X-Ray; Cysteine Proteinase Inhibitors|ME; Glycosylation; Lysosomes|EN; Models, Molecular; Molecular Sequence Data; Oligosaccharides|CH; Protein Precursors|CH; Protein Processing, Post-Translational|PH; Protein Structure, Secondary; Sequence Alignment; Support, Non-U.S. Gov't; Swine

Publication Type

JOURNAL ARTICLE

ISSN

0969-2126

Country of Publication

ENGLAND

Record 36 from database: MEDLINE
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Title

Characterization of recombinant rat cathepsin B and nonglycosylated mutants expressed in yeast. New insights into the pH dependence of cathepsin B-catalyzed hydrolyses.

Author

Hasnain S; Hirama T; Tam A; Mort JS

Address

Protein Structure and Design Section, National Research Council of Canada, Ottawa, Ontario.

Source

J Biol Chem, 1992 Mar, 267:7, 4713-21

Abstract

The cysteine proteinase rat cathepsin B was expressed in yeast in an active form and was found to be heterogeneously glycosylated at the consensus sequence for N-linked oligosaccharide substitution. Purified enzyme fractions containing the highest levels of glycosylation were shown to have reduced activity. A glycosylation minus mutant constructed by site-directed mutagenesis (by changing the Ser to Ala in the consensus sequence) was still secreted by the yeast and was shown to be functionally identical with purified rat liver cathepsin B. Recombinant cathepsin B was used to further characterize the pH dependence of cathepsin B-catalyzed hydrolyses using 7-amido-4-methylcoumarin (AMC) and p-nitroaniline (pNA) substrates with arginine as the P1, and either arginine or phenylalanine as the P2 residue. The AMC and pNA groups give insights into the leaving group binding site (P') of cathepsin B. These studies show for the first time that at least seven dissociable groups are involved in substrate binding and hydrolysis in cathepsin B activity. Two of these groups, with pKa values of 6.9 and 7.7 in the recombinant enzyme, are in the leaving group binding site and are most likely His110 and His111. The same groups in rat liver cathepsin B have higher pKa values than in recombinant cathepsin B, but have identical function in the two enzymes. Two other groups are probably the active site Cys29 and His199 with pKa values of 3.6 and 8.6, respectively. A group with a pKa of 5.1 interacts with substrates containing Arg at P2, and the group is most likely Glu245. The remaining two groups, one with a pKa of about 4.9 and the other about 5.3, are most likely carboxyl residues possibly interacting with Arg at P1 in the substrate. The possible candidates on the basis of the x-ray structure are Asp22, Asp69, Glu171, and Glu122, all found within a 13 A radius from the active site thiol of Cys29.

Language of Publication

English

Unique Identifier

92165832

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MeSH Heading (Major)

Cathepsin B|*GE/ME; Mutation|*; Saccharomyces cerevisiae|*EN

MeSH Heading

Animal; Catalysis; Cloning, Molecular; Electrophoresis, Polyacrylamide Gel; Gene Expression; Glycosylation; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Liver|EN; Rats; Recombinant Proteins|GE/ME; Substrate Specificity; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 37 from database: MEDLINE
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Title

Adsorption and helical coiling of amphipathic peptides on lipid vesicles leads to negligible protection from cathepsin B or cathepsin D.

Author

Goldschmidt TG; Reyes VE; You G; Nelson DJ; Reisert PS; Anderson J; Mole J; Humphreys RE

Address

Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.

Source

Immunol Invest, 1993 Feb, 22:1, 25-40

Abstract

The processing of antigenic peptides for presentation by MHC molecules to T cells, may depend upon the function of a second, consensus sequence in or near the T cell-presented epitope. One such processing-regulating sequence appears to be composed of amino acids Leu, Ile, Val, Phe, and Met recurring in a fashion to form a longitudinal, hydrophobic strip when the excised peptide is coiled as an alpha-helix. Such a hydrophobic strip-of-helix may: (a) scavenge peptides from lumens onto lipid membranes of digestion vesicles, (b) stabilize peptides there as protease-resistant helices, (c) specify recognition by the antigenic peptide-binding sites of chaperonin proteins, transmembranal transporters, or MHC molecules. By circular dichroism and electron paramagnetic resonance, we demonstrated that peptides with recurrent hydrophobic residues potentially forming longitudinal strips adsorbed to, and partially coiled as helices on, di-O-hexadecyl, D-L-alpha-phosphatidylcholine (DHPC) vesicles. Cathepsin B or cathepsin D cleavages of three such peptides were identified. With either enzyme, it made no significant difference whether a peptide substrate was in solution or bound to vesicles in terms of efficiency and specificity of peptide bond cleavages. We conclude that protease resistance, per se, of membrane-adsorbed, helically coiled peptides is not a major factor in the selection for T cell presentation of epitopes in peptides which have a motif with a longitudinal hydrophobic strip.

Language of Publication

English

Unique Identifier

93179049

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MeSH Heading (Major)

Cathepsin B|*ME; Cathepsin D|*ME; Liposomes|*; Peptide Fragments|*CH/DE; Protein Structure, Secondary|*

MeSH Heading

Adsorption; Amino Acid Sequence; Animal; Antigen-Presenting Cells|ME; Electron Spin Resonance Spectroscopy; Molecular Sequence Data; Phospholipid Ethers; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0882-0139

Country of Publication

UNITED STATES

Record 38 from database: MEDLINE
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Title

Dissection of laminin by cathepsin G into its long-arm and short-arm structures and localization of regions involved in calcium dependent stabilization and self-association.

Author

Bruch M; Landwehr R; Engel J

Address

Abteilung Biophysikalische Chemie, Biozentrum der UniversitÂat, Basel, Switzerland.

Source

Eur J Biochem, 1989 Nov, 185:2, 271-9

Abstract

Native laminin-nidogen complex isolated from mouse Engelbreth-Holm-Swarm tumor was treated with purified cathepsin G or leucocyte elastase, two neutral serine proteases which play a role in inflammatory processes accompanied by degradation of basement membranes. Both enzymes were found to be more active than porcine pancreatic elastase. In the absence of Ca2+, laminin fragments produced by leucocyte elastase resembled those formed by the pancreatic enzyme but at physiological concentrations of Ca2+ cleavage by cathepsin G was much more selective. Initially laminin (900 kDa) was cleaved at two major sites only with similar rates leading to three fragments. Fragment C1-4 (about 550 kDa) comprises the intact three short arms of the molecule and fragment C8-9 (about 350 kDa) contains the entire triple-coiled region by which its three chains are assembled and the major part of the terminal globular domain of the long arm. The remaining C-terminal region of this domain was recovered as fragment C3 of about 50 kDa. Stabilization against proteolytic attack was restricted to the region of fragment C1-4 and only this fragment exhibited strong Ca2+ dependent self-association similar to that of intact laminin or of its complex with nidogen. The associative properties of fragment C1-4 were dramatically diminished upon removal of the tip of one of the short arms comprising fragment 4. In addition, this provides a clear assignment of the important laminin function to a distinct domain in one of its short arms. The new fragment C8-9 may be employed for exploring the properties and possible functions of the upper long-arm region which so far has not been available as a fragment.

Language of Publication

English

Unique Identifier

90060110

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MeSH Heading (Major)

Calcium|*ME; Cathepsins|*PD; Laminin|*ME/UL

MeSH Heading

Animal; Human; Membrane Proteins|ME; Mice; Molecular Weight; Pancreatic Elastase|PD; Peptide Fragments|ME; Protein Conformation; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0014-2956

Country of Publication

GERMANY, WEST

Record 39 from database: MEDLINE
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Title

Human leukocyte cathepsin G and elastase specifically suppress thrombin-induced prostacyclin production in human endothelial cells.

Author

Weksler BB; Jaffe EA; Brower MS; Cole OF

Address

Department of Medicine, Cornell University Medical College, New York, NY.

Source

Blood, 1989 Oct, 74:5, 1627-34

Abstract

Polymorphonuclear leukocytes (PMN) when activated release products that can potentially injure endothelial cells or alter endothelial function. Exposure of cultured human umbilical vein endothelial cells to cathepsin G and elastase isolated from human PMN at concentrations reached in vivo (100 ng/mL to 10 micrograms/mL) selectively inhibited thrombin-induced prostacyclin production and the thrombin-induced rise in cytosolic free calcium ([Ca++]i) concentration. These proteases also blocked thrombin-induced release of arachidonic acid from prelabeled endothelial cells (EC). In contrast, induction of prostacyclin (PGI2) production by arachidonate, histamine, or the calcium ionophore A23187 was not altered by treatment of EC with these proteases. The effects of the proteases were concentration-dependent, were blocked by serum or serum protease inhibitors, and were reversed when the endothelial cells were further cultured for 24 hours in the absence of the proteases. Elastase, but not cathepsin G, also produced detachment of endothelial cells. Thus, the major leukocyte proteases selectively suppress thrombin-induced prostacyclin production by human vascular endothelial cells and may alter the hemostatic balance at sites of PMN activation.

Language of Publication

English

Unique Identifier

90001545

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MeSH Heading (Major)

Cathepsins|*BL/IP; Endothelium, Vascular|DE/*ME; Epoprostenol|*BI; Leukocytes|*EN; Pancreatic Elastase|*BL/IP; Thrombin|*PH

MeSH Heading

alpha 1-Antitrypsin|PH; alpha-Macroglobulins|PH; Arachidonic Acids|ME; Calcimycin|PD; Calcium|ME; Cells, Cultured; Human; Kinetics; Neutrophils|EN; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-4971

Country of Publication

UNITED STATES

Record 40 from database: MEDLINE
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Title

Neutrophil elastase and cathepsin G: structure, function, and biological control.

Author

Watorek W; Farley D; Salvesen G; Travis J

Address

Department of Biochemistry, University of Georgia, Athens 30602.

Source

Adv Exp Med Biol, 1988, 240:, 23-31

Abstract

When neutrophils invade inflamed areas of the body to remove either dead or foreign components they inadvertently release potent enzymes which can, if not properly controlled, cause severe damage to healthy tissue. This can lead to a myriad of diseases including emphysema, rheumatoid arthritis, and glomuerlopnephritis, all of which are really problems of abnormal connective tissue turnover due to uncontrolled protelysis by neutrophil elastase and cathepsin G. An important step in elucidating the functions of both elastase and cathepsin G has been made by virtue of the fact that the amino acid sequence of each has been determined. Furthermore, the crystal structure of one, neutrophil elastase, is now understood. With this knowledge in mind and with the potential for a similar understanding of the mechanism of action of cathepsin G, it should soon be possible to produce synthetic inhibitors of each enzyme which can act as adjunct inhibitors to those naturally circulating in the blood or present in other tissues. As a result there is great hope for reducing the severity of injury produced by these enzymes and, therefore, in decreasing the risk for development of the debilitating diseases associated with abnormal proteolysis by neutrophil proteinases.

Language of Publication

English

Unique Identifier

89225435

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MeSH Heading (Major)

Cathepsins|*PH; Neutrophils|*EN; Pancreatic Elastase|*PH

MeSH Heading

Amino Acid Sequence; Blood Proteins; Carbohydrates|AN; Human; Molecular Sequence Data; Serine Endopeptidases|ME; Structure-Activity Relationship; Substrate Specificity; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0065-2598

Country of Publication

UNITED STATES

Record 41 from database: MEDLINE
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Title

Cathepsin D inactivates cysteine proteinase inhibitors, cystatins.

Author

Lenarcic B; Kos J; Dolenc I; Lucovnik P; Krizaj I; Turk V

Address

Department of Biochemistry, J. Stefan Institute, Ljubljana, Yugoslavia.

Source

Biochem Biophys Res Commun, 1988 Jul, 154:2, 765-72

Abstract

The formation of inactive complexes in excess molar amounts of human cathepsins H and L with their protein inhibitors human stefin A, human stefin B and chicken cystatin at pH 5.6 has been shown by measurement of enzyme activity coupled with reverse-phase HPLC not to involve covalent cleavage of the inhibitors. Inhibition must be the direct result of binding. On the contrary the interaction of cystatins with aspartic proteinase cathepsin D at pH 3.5 for 60 min followed by HPLC resulted in their inactivation accompanied by peptide bond cleavage at several sites, preferentially those involving hydrophobic amino acid residues. The released peptides do not inhibit papain and cathepsin L. These results explain reported elevated levels of cysteine proteinases and lead to the proposal that cathepsin D exerts an important function, through inactivation of cystatins, in the increased activities of cysteine proteinases in human diseases including muscular distrophy.

Language of Publication

English

Unique Identifier

88293513

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MeSH Heading (Major)

Cathepsin D|*ME; Cysteine Endopeptidases|*AI; Protease Inhibitors|*; Proteins|*AI

MeSH Heading

Amino Acid Sequence; Chromatography, High Pressure Liquid; Human; Molecular Sequence Data; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0006-291X

Country of Publication

UNITED STATES

Record 42 from database: MEDLINE
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Title

Cathepsin B and L in isolated proximal tubular segments during acute and chronic proteinuria.

Author

Eisenberger U; Fels LM; Olbricht CJ; Stolte H

Address

Department of Internal Medicine, Hannover Medical School, Germany.

Source

Ren Physiol Biochem, 1995 Mar, 18:2, 89-96

Abstract

Acute and chronic proteinuria were studied in rats, using lysosomal cathepsin B and L as marker enzymes for tubular protein degradation. The activity of cathepsin B and L has been determined in microdissected segments S1, S2 and S3 of the proximal tubule by an ultramicroassay. Z-Phenylalanyl-arginine-7-amido-4-methylcoumarin served as a substrate. In normoproteinuric Sprague-Dawley rats, induction of acute unselective glomerular proteinuria with Adriamycin (5 mg/kg body weight) revealed a moderate activity increase of cathepsin B and L in the S2 segment, reaching 12.6 +/- 5.6 versus 8.6 +/- 4.2 pmol.mm-1.min-1 in controls. In contrast, Munich Wistar Frömter (MWF) rats, that are characterized by a genetically determined, chronically elevated glomerular protein excretion, showed a very high activity of cathepsin selectively in S2 of 25.0 +/- 12.1 pmol.mm-1.min-1. Acute proteinuria induced by Adriamycin in chronic proteinuric MWF rats could increase cathepsin activity in the S3 segment only, showing 12.0 +/- 8.3 versus 6.8 +/- 4.0 pmol.mm-1.min-1 in MWF control rats. In conclusion, chronically increased protein filtration changes the functional reserve capacity of the proximal tubule. While acutely induced glomerular proteinuria in normoproteinuric rats stimulates lysosomal proteolytic activity mainly in S2 segment, chronic proteinuric MWF rats may display already a maximally stimulated cathepsin activity in this segment probably due to long-term increased tubular protein load. In case of acute elevation of chronic proteinuria, the consecutive S3 segment shows increased lysosomal function for protein conservation.

Language of Publication

English

Unique Identifier

95288517

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MeSH Heading (Major)

Cathepsin B|*ME; Cathepsins|*ME; Kidney Tubules, Proximal|*EN; Proteinuria|CI/GE/*ME

MeSH Heading

Acute Disease; Animal; Chronic Disease; Comparative Study; Creatinine|UR; Doxorubicin; Female; Nephrosis|CI/ME; Rats; Rats, Inbred WF; Rats, Sprague-Dawley; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

1011-6524

Country of Publication

SWITZERLAND

Record 43 from database: MEDLINE
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Title

Regulation of cathepsin E expression during human B cell differentiation in vitro.

Author

Sealy L; Mota F; Rayment N; Tatnell P; Kay J; Chain B

Address

Department of Immunology, UCL Medical School, London, GB.

Source

Eur J Immunol, 1996 Aug, 26:8, 1838-43

Abstract

Cathepsin E is an aspartic proteinase which has been implicated in antigen processing in the class II major histocompatibility complex pathway. In this study we show that cathepsin E, measured at both the protein and message level, is up-regulated late in human B cell activation. The implications of this observation in terms of cathepsin E function are discussed.

Language of Publication

English

Unique Identifier

96350506

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MeSH Heading (Major)

B-Lymphocytes|*IM/*ME; Cathepsins|*BI/GE

MeSH Heading

Adolescence; Adult; Base Sequence; Cell Differentiation|GE/IM; Cell Line; Child; Child, Preschool; Epitopes|IM; Human; Infant; Lymphocyte Transformation; Molecular Sequence Data; RNA, Messenger|AN; T-Lymphocytes|IM; Tonsil

Publication Type

JOURNAL ARTICLE

ISSN

0014-2980

Country of Publication

GERMANY

Record 44 from database: MEDLINE
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Title

Expression, subcellular distribution and plasma membrane binding of cathepsin B and gelatinases in bone metastatic tissue.

Author

Arkona C; Wiederanders B

Address

Institute of Biochemistry, Medical Faculty, Friedrich-Schiller-University, Jena, Germany.

Source

Biol Chem, 1996 Nov, 377:11, 695-702

Abstract

The possible application of proteinase inhibitors in the support of anti-tumor chemotherapy requires profound knowledge of the proteinases involved in malignant processes. Therefore, the occurrence of cathepsins B, D, H, L and S and of gelatinases, urokinase plasminogen activator and stromelysins was studied in biopsies of aggressive human bone metastases, of low invading basal cell carcinomas, and in normal placenta as control, by activity measurements and zymographic techniques. Cathepsin B and L, as well as gelatinase B, were shown to be overexpressed in bone metastases, suggesting a function during the metastatic process. Subcellular fractionation allowed detection of differential sorting of cathepsin B and gelatinases in metastatic tissue and also in normal human placenta. Plasma membrane binding could be demonstrated for both cathepsin B and gelatinase B. Whereas cathepsin B is at least partially bound to plasma membranes via alpha 2-macroglobulin and its LRP/alpha 2-macroglobulin receptor, gelatinase B binds to plasma membranes by an unknown mechanism.

Language of Publication

English

Unique Identifier

97119547

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MeSH Heading (Major)

Bone Neoplasms|EN/*SC; Cathepsin B|*ME; Gelatinases|*ME

MeSH Heading

beta-N-Acetylhexosaminidase|ME; Acid Phosphatase|ME; Cathepsins|ME; Cell Membrane|EN; Collagenases|ME; Human; Lactate Dehydrogenase|ME; Neoplasm Metastasis; Phosphotransferases (Alcohol Group Acceptor)|ME; Subcellular Fractions|EN; Support, Non-U.S. Gov't; Urokinase|ME; 5'-Nucleotidase|ME

Publication Type

JOURNAL ARTICLE

ISSN

1431-6730

Country of Publication

GERMANY

Record 45 from database: MEDLINE
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Title

Effects of in vitro cellular aging on alkaline phosphatase, cathepsin activities and collagen secretion of human periodontal ligament derived cells.

Author

Goseki T; Shimizu N; Iwasawa T; Takiguchi H; Abiko Y

Address

Department of Orthodontics, Nihon University School of Dentistry at Matsudo, Chiba, Japan.

Source

Mech Ageing Dev, 1996 Nov, 91:3, 171-83

Abstract

It is believed that the degree of periodontal tissue breakdown and tooth loss increase with age. In periodontal tissues which are gingiva, periodontal ligament (PL), alveolar bone and tooth cementum, the PL which is soft connective tissue, lies between the tooth cementum and alveolar bone, having the primary function of tooth support, and maintaining the homeostasis of supporting tissues, as well as providing the healing process. We therefore investigated the effects of in vitro cellular aging on alkaline phosphatase (ALP), cathepsin activities and collagen secretion from human PL cells obtained from 18-23 year-old patients' teeth. ALP, cathepsin activities and collagen secretion may play important roles in the remodeling and maintaining of periodontal tissues. To investigate the life span of PL cells, the cells were sequentially subcultivated. The maximum population doubling level of the PL cells in the present experiment was 22-25 passages. Investigating some important biological activities of the PL cells at different passage levels (6-7, 30% of life span to 17-20, 75% of life span), ALP activity and collagen secretion were found to have significantly decreased while cathepsin B and L activities significantly increased with cellular aging. Since these biological activities in human PL cells tend to be more catabolic with increase in cellular aging, the increase in periodontal breakdown with age may be partly related to the catabolic changes of the PL cells themselves.

Language of Publication

English

Unique Identifier

97208005

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MeSH Heading (Major)

Alkaline Phosphatase|*ME; Cathepsin B|*ME; Cathepsins|*ME; Collagen|*SE; Periodontal Ligament|CY/*ME

MeSH Heading

Adolescence; Adult; Cell Aging; Cell Division; Female; Human; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0047-6374

Country of Publication

IRELAND

Record 46 from database: MEDLINE
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Title

Novel potential mechanism-based inhibitors of human leukocyte elastase and cathepsin G: derivatives of isothiazolidin-3-one.

Author

Groutas WC; Chong LS; Venkataraman R

Address

Department of Chemistry, Wichita State University, KS 67260.

Source

Biochem Biophys Res Commun, 1993 Dec, 197:2, 730-9

Abstract

A series of heterocyclic compounds designed to function as mechanism-based inhibitors of human leukocyte elastase and cathepsin G has been synthesized and their inhibitory activity was investigated. These isothiazolidin-3-one derivatives were found to be effective inhibitors of cathepsin G.

Language of Publication

English

Unique Identifier

94092155

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MeSH Heading (Major)

Cathepsins|*AI/BL; Leukocytes|*EN; Pancreatic Elastase|*AI; Protease Inhibitors|CS/*PD; Thiazoles|CS/*PD

MeSH Heading

Comparative Study; Human; Kinetics; Molecular Structure; Structure-Activity Relationship; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-291X

Country of Publication

UNITED STATES

Record 47 from database: MEDLINE
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Title

Lipid-rich residual bodies and cathepsin D in the human uterus: ultrastructural and quantitative comparison between normal myometrium and leiomyoma.

Author

Yamazaki K; Yakumaru K; Eyden BP

Address

Department of Pathology, Tokyo Teishin Hospital, Japan.

Source

J Submicrosc Cytol Pathol, 1993 Jul, 25:3, 437-47

Abstract

The lipid-rich residual bodies (LRRB) (Eyden et al., 1991) in human myometrium and uterine leiomyoma cells, have a distinctive ultrastructure characterised by a rich lipid content. To evaluate the biological or pathological significance in detail, normal myometrium and uterine leiomyoma from 30 human cases were studied by conventional histological, histochemical, immunohistochemical and electron microscopic methods. The study included a quantitative analysis of LRRBs of 3 premenarchic cases, 19 cases having a menstrual cycle, and 8 cases in menopause, in addition to 20 patients with histologically conventional leiomyoma larger than 3 cm in diameter. The study revealed the following findings: 1) immunohistochemical distribution of cathepsin D in the LRRB; 2) histochemical demonstration of neutral fat as the main content of LRRB; 3) statistically significant decrease in the distribution of LRRB in leiomyoma tissue compared with normal myometrium; 4) an absence or minimal distribution of LRRB in premenarchic myometrium; 5) a moderately significant correlation between the frequency of LRRB and patient's age. The distribution of cathepsin D within LRRB and the differential expression of LRRBs in the various smooth muscle cell tissues of the uterus suggest a possible role of ovarian hormones in the genesis of LRRBs which may function in the intra-lysosomal degradation of organelles produced during hormonal cycling.

Language of Publication

English

Unique Identifier

94006142

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MeSH Heading (Major)

Cathepsin D|*AN/ME; Inclusion Bodies|*CH/UL; Leiomyoma|*CH/PA/UL; Lipids|*AN/ME; Myometrium|*CH/CY/UL; Uterine Neoplasms|*CH/PA/UL; Uterus|*CH/CY/PA

MeSH Heading

Adolescence; Adult; Aged; Aged, 80 and over; Aging|ME/PH; Child; Comparative Study; Female; Human; Immunohistochemistry; Infant, Newborn; Menopause|PH; Menstrual Cycle|PH; Microscopy, Electron; Middle Age; Organelles|UL

Publication Type

JOURNAL ARTICLE

ISSN

1122-9497

Country of Publication

ITALY

Record 48 from database: MEDLINE
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Title

Expression and partial characterization of a cathepsin B-like enzyme (Sm31) and a proposed 'haemoglobinase' (Sm32) from Schistosoma mansoni.

Author

Götz B; Klinkert MQ

Address

Institute of Cell Biology, Consiglio Nazionale delle Ricerche, Rome, Italy.

Source

Biochem J, 1993 Mar, 290 ( Pt 3):, 801-6

Abstract

Schistosoma mansoni protein Sm31 is a cysteine proteinase similar to mammalian lysosomal cathepsin B, proposed to be a key enzyme in schistosome metabolism. Protein Sm32 has been identified as a putative cysteine proteinase termed a 'haemoglobinase'. Since neither Sm31 nor Sm32 have been completely purified, some controversy of the nature of the 'true' digestive enzyme still exists. By incubating a radiolabelled cysteine-proteinase active-site-directed synthetic inhibitor with total S. mansoni proteins, the target of inhibition was Sm31 and not Sm32. The selectivity and irreversibility of inactivation make affinity labelling an invaluable tool for exploring key differences among closely related enzymes and also for studying proteinase activity in a cellular environment. In order to confirm these results, we expressed the complete cDNA sequences of Sm31 and Sm32 in insect cells and analysed the recombinant gene products for proteolytic activities. Cell extracts containing S. mansoni cathepsin B, but not those expressing 'haemoglobinase', were demonstrated to cleave a synthetic substrate benzyloxycarbonyl-arginylarginylaminomethylcoumarin in fluorescence assays. Our findings confirm previous assertions that a cysteine proteinase resembling cathepsin B is the haemoglobinase involved in digestion of host proteins. Thus, the original proposal that Sm32 is a cysteine proteinase has not been verified, and its function remains unknown.

Language of Publication

English

Unique Identifier

93207533

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MeSH Heading (Major)

Cathepsin B|CH/*GE/ME; Cysteine Endopeptidases|CH/*GE/ME; Gene Expression|*; Helminth Proteins|*GE/ME; Schistosoma mansoni|*EN

MeSH Heading

Amino Acid Sequence; Animal; Baculoviridae|GE; Binding Sites; Cell Line; Cloning, Molecular; Coumarins|ME; Dipeptides|ME; Hemoglobins|ME; Hydrolysis; Immunoblotting; Molecular Sequence Data; Moths|ME; Recombinant Proteins|CH/ME; Substrate Specificity; Support, Non-U.S. Gov't; Transfection

Publication Type

JOURNAL ARTICLE

ISSN

0264-6021

Country of Publication

ENGLAND

Record 49 from database: MEDLINE
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Title

Exploration of subsite binding specificity of human cathepsin D through kinetics and rule-based molecular modeling.

Author

Scarborough PE; Guruprasad K; Topham C; Richo GR; Conner GE; Blundell TL; Dunn BM

Address

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville 32610.

Source

Protein Sci, 1993 Feb, 2:2, 264-76

Abstract

The family of aspartic proteinases includes several human enzymes that may play roles in both physiological and pathophysiological processes. The human lysosomal aspartic proteinase cathepsin D is thought to function in the normal degradation of intracellular and endocytosed proteins but has also emerged as a prognostic indicator of breast tumor invasiveness. Presented here are results from a continuing effort to elucidate the factors that contribute to specificity of ligand binding at individual subsites within the cathepsin D active site. The synthetic peptide Lys-Pro-Ile-Glu-Phe*Nph-Arg-Leu has proven to be an excellent chromogenic substrate for cathepsin D yielding a value of kcat/Km = 0.92 x 10(-6) s-1 M-1 for enzyme isolated from human placenta. In contrast, the peptide Lys-Pro-Ala-Lys-Phe*Nph-Arg-Leu and all derivatives with Ala-Lys in the P3-P2 positions are either not cleaved at all or cleaved with extremely poor efficiency. To explore the binding requirements of the S3 and S2 subsites of cathepsin D, a series of synthetic peptides was prepared with systematic replacements at the P2 position fixing either Ile or Ala in P3. Kinetic parameters were determined using both human placenta cathepsin D and recombinant human fibroblast cathepsin D expressed in Escherichia coli. A rule-based structural model of human cathepsin D, constructed on the basis of known three-dimensional structures of other aspartic proteinases, was utilized in an effort to rationalize the observed substrate selectivity.

Language of Publication

English

Unique Identifier

93184744

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MeSH Heading (Major)

Cathepsin D|CH/GE/*ME; Chromogenic Compounds|CH/*ME; Oligopeptides|CH/*ME

MeSH Heading

Amino Acid Sequence; Aspartic Endopeptidases|ME; Computer Simulation; Escherichia coli|GE; Fibroblasts|EN; Human; Kinetics; Models, Molecular; Molecular Sequence Data; Placenta|EN; Protease Inhibitors|ME; Recombinant Proteins|ME; Structure-Activity Relationship; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0961-8368

Country of Publication

UNITED STATES

Record 50 from database: MEDLINE
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Title

Cathepsin B expression in human tumors.

Author

Berquin IM; Sloane BF

Address

Wayne State University, Department of Pharmacology, Detroit, Michigan 48201, USA.

Source

Adv Exp Med Biol, 1996, 389:, 281-94

Abstract

Cathepsin B has been linked to tumor progression through observations that its activity, secretion or membrane association are increased. The most malignant tumors, and specifically the cells at the invasive edge of those tumors, express the highest activity. Cathepsin B may facilitate invasion directly by dissolving extracellular matrix barriers like the basement membrane, or indirectly by activating other proteases capable of digesting the extracellular matrix. Cathepsin B also might play a role in tumor growth and angiogenesis. Cathepsin B activity is the result of several levels of regulation: transcription, post-transcription processing, translation and glycosylation, maturation and trafficking, and inhibition. The majority of reports on cathepsin B expression in tumors have focused on measurements of activity or protein staining. In some tumors, e.g. gliomas, a correlation between the amounts of cathepsin B mRNA, protein and activity and tumor progression has been established. Regulation of cathepsin B at the transcriptional and post-transcriptional levels is still poorly understood. Although the putative promoter regions have characteristics of housekeeping-type promoters, cathepsin B mRNA expression varies depending on the cell type and state of differentiation. We have evidence that more than one promoter could direct expression of human cathepsin B. Multiple transcript species have been detected, resulting from alternative splicing in the 5'- or 3'-untranslated regions, and possibly the use of alternative promoter regions. The existence of transcript variants indicates a potential for post-transcriptional control of expression. In support of this, ras-transformation of MCF-10A human breast epithelial cells results in an increase in protein levels without a concomitant increase in mRNA levels. Cathepsin B mRNA species with distinct 5'- or 3'-untranslated regions may differ in their stability and translatability. Variations in the coding region may also alter cathepsin B properties. We and Frankfater's group have observed transcript species that would encode a truncated protein, lacking the prepeptide and about half of the propeptide. This truncated protein, if synthesized in cells, would be expected to be cytosolic; therefore its function is unclear. Once the several mechanisms of regulation of cathepsin B expression and activity are better understood, they could provide us with new strategies to specifically reduce cathepsin B activity in tumors.

Language of Publication

English

Unique Identifier

97014187

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MeSH Heading (Major)

Cathepsin B|*BI/GE; Neoplasms|*EN/PA; Tumor Markers, Biological|*AN

MeSH Heading

Disease Progression; Gene Expression Regulation, Neoplastic|PH; Human; Organ Specificity; RNA, Messenger|GE; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0065-2598

Country of Publication

UNITED STATES

Record 51 from database: MEDLINE
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Title

Thrombin- and cathepsin G-induced platelet aggregation: effect of protein kinase C inhibitors.

Author

Puri RN; Colman RW

Address

Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.

Source

Anal Biochem, 1993 Apr, 210:1, 50-7

Abstract

Two serine proteases, thrombin and cathepsin G, are potent agonists of human platelet activation. These pathophysiological proteases induce similar platelet responses, e.g., aggregation, shape change, and secretion of the dense granules. Maintenance of proteolytic function and the ability to bind to receptors on the platelet surface membrane are required for the responses elicited by both proteases. Protein kinase C (PKC) is a signal-transducing enzyme that is an important regulator of postreceptor intracellular changes following exposure of platelets to thrombin and cathepsin G. Inhibitors of purified PKC, e.g., staurosporine and calphostin C, have been frequently used to elucidate biochemical mechanisms mediated by the intracellular PKC following platelet activation by proteases. However, the effect of the PKC inhibitors on the amidolytic activity and on the ability of the two bioregulatory proteases to bind to cells has never been investigated. We found that staurosporine (1 and 1.5 microM), calphostin C (10 and 60 microM), and fisetin (200 and 220 microM), the three most commonly used and biochemically well-characterized inhibitors of purified PKC, completely inhibited thrombin-induced (2 nM) and cathepsin G-induced (0.85 microM) aggregation of washed human platelets, respectively. Each of the three PKC inhibitors completely blocked platelet shape change induced by thrombin (1 nM). Only fisetin inhibited platelet shape change induced by cathepsin G (0.5 microM). Only fisetin partially inhibited amidolytic activity of thrombin. The three PKC inhibitors had no inhibitory effect on the amidolytic activity of those concentrations of cathepsin G that cause maximum platelet aggregation and platelet shape change. The three PKC inhibitors completely blocked binding of 125I-thrombin to washed platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

93256284

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MeSH Heading (Major)

Cathepsins|ME/*PD; Platelet Aggregation|*DE/PH; Protein Kinase C|*AI/PH; Thrombin|ME/*PD

MeSH Heading

Alkaloids|PD; Amino Acid Sequence; Blood Platelets|CY/DE/ME; Flavones|PD; Human; In Vitro; Molecular Sequence Data; Oligopeptides|CH; Polycyclic Hydrocarbons|PD; Substrate Specificity; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0003-2697

Country of Publication

UNITED STATES

Record 52 from database: MEDLINE
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Title

Processing of beta-amyloid precursor protein by cathepsin D.

Author

Higaki J; Catalano R; Guzzetta AW; Quon D; Navé JF; Tarnus C; DOrchymont H; Cordell B

Address

Scios, Inc., Mountain View, California 94043, USA.

Source

J Biol Chem, 1996 Dec, 271:50, 31885-93

Abstract

The events leading to the formation of beta-amyloid (betaA4) from its precursor (betaAPP) involve proteolytic cleavages that produce the amino and carboxyl termini of betaA4. The enzyme activities responsible for these cleavages have been termed beta- and gamma-secretase, respectively, although these protease(s) have not been identified. Since betaA4 is known to possess heterogeneity at both the amino and carboxyl termini, beta- and gamma-secretases may actually be a collection of proteolytic activities or perhaps a single proteolytic enzyme with broad amino acid specificity. We investigated the role of cathepsin D in the processing of betaAPP since this enzyme has been widely proposed as a gamma-secretase candidate. Treatment of a synthetic peptide that spans the gamma-secretase site of betaAPP with human cathepsin D resulted in the cleavage of this substrate at Ala42-Thr43. A sensitive liquid chromatography/mass spectrometry technique was also developed to further investigate the ability of cathepsin D to process longer recombinant betaAPP substrates (156 and 100 amino acids of betaAPP carboxyl terminus) in vitro. The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. No cleavages were observed at putative gamma-secretase sites: Val40-Ile41 or Ala42-Thr43, suggesting that cathepsin D is not gamma-secretase as defined by these betaA4 termini. Under conditions where the betaAPP156 substrate was first denatured prior to cathepsin D digestion, two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.

Language of Publication

English

Unique Identifier

97112979

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MeSH Heading (Major)

Amyloid beta-Protein Precursor|*ME; Cathepsin D|*ME

MeSH Heading

Amino Acid Sequence; Blotting, Western; Chromatography, High Pressure Liquid; Human; Molecular Sequence Data; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 53 from database: MEDLINE
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Title

Cathepsin D serum mass concentrations in patients with hepatocellular carcinoma and/or liver cirrhosis.

Author

Leto G; Tumminello FM; Pizzolanti G; Montalto G; Soresi M; Ruggeri I; Gebbia N

Address

Servizio di Chemioterapia, FacoltÄa di Medicina e Chirurgia, UniversitÄa di Palermo, Italy.

Source

Eur J Clin Chem Clin Biochem, 1996 Jul, 34:7, 555-60

Abstract

Cathepsin D serum mass concentrations were determined by enzyme immunoassay in patients with hepatocellular carcinoma (n = 51) and/or liver cirrhosis (n = 92) or benign steatosis (n = 16) and correlated with some biochemical and clinical properties of these diseases. Increased cathepsin D serum mass concentrations (P < 0.001) were observed in all these groups of patients as compared to normal subjects (n = 98). However, patients with steatosis had serum mass concentrations of this enzyme significantly lower (mean 2-3 fold) than those measured in cancer patients (P < 0.05) or cirrhotic patients (P < 0.001). Interestingly, significantly higher cathepsin D serum mass concentrations (mean + 62%) (P < 0.006) were determined in the cirrhosis group as compared to cancer patients. No correlation between cathepsin D and a number of clinical and biochemical properties examined, namely, alpha-foetoprotein, number of neoplastic lesions and tumour size in cancer patients or, Child-Pugh grade of severity of cirrhosis and other enzymes of liver function tests in the cirrhotic group was found. The present data and those from other studies which indicate that cathepsin D may be involved in carcinogenesis suggest that this enzyme may be potentially useful as an additional biochemical marker to identify cirrhotic patients who may develop precancerous hepatic nodules.

Language of Publication

English

Unique Identifier

97017787

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MeSH Heading (Major)

Carcinoma, Hepatocellular|*EN; Cathepsin D|*BL; Liver Cirrhosis|*EN; Liver Neoplasms|*EN

MeSH Heading

alpha-Fetoproteins|AN; Adult; Aged; Female; Hepatitis, Alcoholic|EN; Human; Immunoenzyme Techniques; Male; Middle Age; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0939-4974

Country of Publication

GERMANY

Record 54 from database: MEDLINE
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Title

Cathepsin L proteinase secreted by Fasciola hepatica in vitro prevents antibody-mediated eosinophil attachment to newly excysted juveniles.

Author

Carmona C; Dowd AJ; Smith AM; Dalton JP

Address

School of Biological Sciences, Dublin City University, Glasnevin, Ireland.

Source

Mol Biochem Parasitol, 1993 Nov, 62:1, 9-17

Abstract

Cathepsin L-like activity was demonstrated in the excretory/secretory (E/S) products of Fasciola hepatica newly excysted juveniles (NEJ), 3-week-old, 5-week-old and mature flukes using the fluorogenic substituted 7-amino-4-methylcoumarin substrates Z-phe-arg-AMC, Z-arg-arg-AMC and Z-arg-AMC. Gelatin-substrate polyacrylamide gel analysis revealed that the E/S from each of these stages contained multiple proteolytic enzymes; however, the pattern of proteinases obtained for NEJ E/S differed markedly from that of all other stages examined. The four NEJ proteinases identified were inhibited by leupeptin and Z-phe-ala-diazomethyl ketone indicating that each had cathepsin L-like activity. The E/S products of all four developmental stages contain an enzyme capable of cleaving immunoglobulin at the hinge region, the activity of which is also inhibited by Z-phe-ala-diazomethyl ketone. Using in vitro cell attachment assays we show that the cathepsin L-like proteinase purified from the E/S products of adult F. hepatica can prevent the antibody-mediated attachment of eosinophil to NEJ. These experiments indicate that this proteinase has an important biological function in immune evasion.

Language of Publication

English

Unique Identifier

94158980

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MeSH Heading (Major)

Antibody-Dependent Cell Cytotoxicity|*; Cathepsins|IM/ME/*SE; Eosinophils|CY/*IM; Fasciola hepatica|*EN/GD/*IM

MeSH Heading

Animal; Cell Adhesion|IM; IgG|ME; In Vitro; Substrate Specificity; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0166-6851

Country of Publication

NETHERLANDS

Record 55 from database: MEDLINE
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Title

Structure, function, regulation and clinical significance of the 52K pro-cathepsin D secreted by breast cancer cells.

Author

Rochefort H; Augereau P; Briozzo P; Capony F; Cavailles V; Freiss G; Garcia M; Maudelonde T; Morisset M; Vignon F

Address

UnitÆe Hormones et Cancer, INSERM U 148, Montpellier, France.

Source

Biochimie, 1988 Jul, 70:7, 943-9

Abstract

In estrogen-receptor-positive human breast cancer cell lines (MCF7, ZR75-1), estrogens specifically increase the secretion into the culture medium of a 52,000 Da (52K) glycoprotein and stimulate cell proliferation. The 52K protein has been purified to homogeneity using monoclonal antibodies and identified as the secreted precursor of a cathepsin D bearing mannose-6-phosphate signals. The secreted precursor 52K protein is mitogenic in vitro in estrogen-deprived MCF7 cells, can be taken up by these cells via mannose-6-phosphate receptors, and can degrade extracellular matrix and proteoglycans following its auto-activation. The protease is also produced constitutively by ER-negative cell lines, and is inducible by tamoxifen in some antiestrogen-resistant variants. The corresponding cDNA has been cloned using N-terminal sequencing of the protein and monoclonal antibodies. Its complete sequencing indicates a strong homology with pro-cathepsin D of normal tissues. Using a cDNA probe, the regulation of 52K cathepsin D mRNA by estrogens and antiestrogens has been studied and chromosome localization determined by in situ hybridization. Clinical studies using both immunohistochemistry and immunoenzymatic assay of breast cancer cytosol have shown that the concentration of total cellular cathepsin D (52K + 48K + 34K) is related to the proliferation of mammary ducts and to the prognosis of breast cancer. Its cytosolic concentration in primary tumors of postmenopausal patients is correlated slightly with lymph node invasion and significantly with shorter disease-free intervals in a 6-year retrospective study with the Danish Breast Cancer Groups and Finsen Institute (S. Thorpe et al.).(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

89088285

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MeSH Heading (Major)

Breast Neoplasms|DI/*EN; Cathepsin D|GE/IP/*SE; Enzyme Precursors|GE/IP/*SE

MeSH Heading

Cell Line; Cell Transformation, Neoplastic; Estrogens|PD; Female; Human; Molecular Weight; Prognosis; Protein Processing, Post-Translational; Support, Non-U.S. Gov't; Translation, Genetic; Tumor Markers, Biological|AN

Publication Type

JOURNAL ARTICLE

ISSN

0300-9084

Country of Publication

FRANCE

Record 56 from database: MEDLINE
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Title

Endometrial cathepsin D immunostaining throughout ovulatory and anovulatory menstrual cycles.

Author

Camier B; Hedon B; Rochefort H; Maudelonde T

Address

Department of Reproductive Biology, Hopital d'Amiens, France.

Source

Hum Reprod, 1996 Feb, 11:2, 392-7

Abstract

The results of histological examination of the endometrium are normal in most patients with unexplained sterility. Cathepsin D is a ubiquitous lysosomal protease regulated by progesterone in the endometrium. Assays of concentrations of cathepsin D might be useful in determining the functional responses of the endometrium to progesterone. To examine this possibility, we quantified immunostaining of endometrial cathepsin D using an image analysis system in women with regular menstrual cycles. An endometrial sample was obtained during the proliferative and luteal phases from 17 women with ovulatory menstrual cycles and at the beginning and during the last 14 days of a cycle from 15 women having anovulatory menstrual cycles. In endometrial glands of ovulatory women, cathepsin D protein immunostaining increased during the cycle and was significantly higher during the luteal than during the proliferative phase [51 +/- 38.1 arbitrary units (AU) versus 118.2 +/- 58.9 AU; P < 0.01]. This increase was also observed in stromal cells, although to a lesser extent (28.6 +/- 26.9 versus 41.5 +/- 43.1 AU; P = NS). In the endometrium of women with anovulatory menstrual cycles, cathepsin D staining was high both for the proliferative and the luteal biopsies in glands (respectively 95 +/- 43 and 104 +/- 51.3 AU) and stromal cells (respectively 61.8 +/- 33.8 and 75 +/- 32.6 AU). In women with ovulatory cycles, cathepsin D staining was localized in the apical part of glandular cells during the proliferative phase and diffused throughout the cytoplasm during the luteal phase. In contrast, in women with anovulatory cycles, cellular localization of cathepsin D remained apical in glands, regardless of the day of biopsy. In conclusion, this study shows that the cytoplasmic localization of cathepsin D might be a qualitative biological indicator of endometrial gland responses to progesterone. This could be a useful tool for evaluating cell function, which is poorly tested by histology alone.

Language of Publication

English

Unique Identifier

96256930

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MeSH Heading (Major)

Anovulation|*PP; Cathepsin D|*ME; Endometrium|CY/*ME; Menstrual Cycle|*; Ovulation|*

MeSH Heading

Adult; Female; Human; Immunohistochemistry; Staining; Support, Non-U.S. Gov't; Tissue Distribution

Publication Type

JOURNAL ARTICLE

ISSN

0268-1161

Country of Publication

ENGLAND

Record 57 from database: MEDLINE
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Title

Schistosoma japonicum: immunocytochemistry of adults using heterologous antiserum to bovine cathepsin D.

Author

Bogitsh BJ; Kirschner KF

Address

Department of Biology, Vanderbilt University, Nashville, Tennessee 37235.

Source

Exp Parasitol, 1987 Oct, 64:2, 213-8

Abstract

Results from previous biochemical and cytochemical studies show that a pepstatin-sensitive hemoglobinase is present in the gastrodermis of adult Schistosoma japonicum. To determine whether there is structural similarity to mammalian cathepsin D in addition to inhibition similarity, an immunocytochemical study was initiated using heterologous antiserum to bovine cathepsin D. With light microscopy, immunostaining was observed in the cecal lumen, the gastrodermis, and on the dorsal tegument and tubercles of male worms. With transmission electron microscopy, immunostaining was observed in gastrodermal autophagosomes and tegumental invaginations of the dorsal tegument of males. Immunostaining was also observed within the tubercles, but the reaction product did not appear to be associated with any definite structure or organelle. Heavy endogenous peroxidase activity in the cecal lumen due to ingested hemoglobin obscured with immunostaining. Assuming that all immunostaining is due to molecules that function in a manner similar to that of cathepsin D, it is suggested that such molecules may regulate some aspect of the host-parasite relationship and/or the parasite's metabolism. Alternatively, the immunostained molecules may be structural proteins with epitopes similar to those of mammalian cathepsin D. Reactions associated with the cecum, however, on the basis of previous studies, are believed to derive from molecules that are proteolytic enzymes.

Language of Publication

English

Unique Identifier

88004968

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MeSH Heading (Major)

Cathepsin D|*IM; Schistosoma japonicum|EN/*IM

MeSH Heading

Animal; Cross Reactions; Immunodiffusion; Immunoenzyme Techniques; Microscopy, Electron; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0014-4894

Country of Publication

UNITED STATES

Record 58 from database: MEDLINE
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Title

Expression of cathepsin G-like and alpha 1-antichymotrypsin-like proteins in reactive astrocytes.

Author

Abraham CR; Kanemaru K; Mucke L

Address

Department of Biochemistry, Boston University School of Medicine, MA 02118-2394.

Source

Brain Res, 1993 Sep, 621:2, 222-32

Abstract

The central nervous system (CNS) of many different species responds to diverse neurologic injuries with an activation of astrocytes. Yet, the exact function of this reactive astrocytosis is unknown. In this report, mouse astrocytes were activated in vivo by focal penetrating brain injury. Reactive astrocytes were stained with antibodies raised against the serine protease cathepsin G (cat.G), the serine protease inhibitor alpha 1-antichymotrypsin (ACT), or the astrocytic marker glial fibrillary acidic protein (GFAP). Reactive astrocytes expressing both cat.G-like and ACT-like antigens were found around cerebral wound margins between 18 h and 13 days after neural lesions. The injury-induced immunostaining was unaltered by 900 rads of total body irradiation, suggesting that the astroglial reaction was relatively independent of bone marrow-derived cells. The in vivo immunostaining was complemented with biochemical assays on cultured primary astrocytes. A synthetic peptide was used as a substrate in combination with specific inhibitors to identify a proteolytic activity within astroglial lysates and culture supernatants that closely resembles cat.G. This activity increased substantially upon stimulation of astrocytes with dibutyryl cyclic AMP and was neutralized by antibodies raised against cat.G. In a separate report, it was shown that astrocytes also contain an ACT-like inhibitory activity. The production of ACT- and cat.G-like antigens and activities by activated astrocytes should allow these cells to participate in a number of important biologic processes. Many of these processes may benefit the CNS by assisting in early wound repair. However, astroglial proteases and their inhibitors could also contribute to the pathogenesis of certain neurologic diseases.

Language of Publication

English

Unique Identifier

94061495

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MeSH Heading (Major)

alpha 1-Antichymotrypsin|*BI; Astrocytes|*ME; Brain Injuries|IM/*ME; Cathepsins|*BI

MeSH Heading

Amino Acid Sequence; Animal; Antigens|BI; Bone Marrow|RE; Comparative Study; Female; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0006-8993

Country of Publication

NETHERLANDS

Record 59 from database: MEDLINE
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Title

Expression of human cathepsin B protein in Escherichia coli.

Author

Chan MM; Fong D

Address

Department of Biological Sciences, Rutgers State University of New Jersey, Piscataway 08855-1059.

Source

FEBS Lett, 1988 Nov, 239:2, 219-22

Abstract

A cDNA fragment containing the coding sequence for the mature enzyme of human lysosomal proteinase cathepsin B was inserted in the pET plasmid expression vectors, so that it was placed under the control of transcription and translation signals from bacteriophage T7. Upon induction, cathepsin B antigen was detected by in situ immunoscreening of lysed E. coli and by Western blot analysis of bacterial lysates. To our knowledge this is the first report of abundant synthesis of cloned cathepsin B in any expression system. Subfragments of cathepsin B can also be generated by this technique and will be used to study cathepsin B structure and function.

Language of Publication

English

Unique Identifier

89031235

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MeSH Heading (Major)

Cathepsin B|*GE; Cloning, Molecular|*; Escherichia coli|*GE

MeSH Heading

Base Sequence; Human; Lysosomes|EN; Molecular Sequence Data; Mutation; Plasmids; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Transcription, Genetic; Translation, Genetic

Publication Type

JOURNAL ARTICLE

ISSN

0014-5793

Country of Publication

NETHERLANDS

Record 60 from database: MEDLINE
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Title

Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha.

Author

Deiss LP; Galinka H; Berissi H; Cohen O; Kimchi A

Address

Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot 76100, Israel.

Source

EMBO J, 1996 Aug, 15:15, 3861-70

Abstract

A functional approach of gene cloning was applied to HeLa cells in an attempt to isolate positive mediators of programmed cell death. The approach was based on random inactivation of genes by transfections with antisense cDNA expression libraries, followed by the selection of cells that survived in the presence of the external apoptotic stimulus. An antisense cDNA fragment identical to human cathepsin D aspartic protease was rescued by this positive selection. The high cathepsin D antisense RNA levels protected the HeLa cells from interferon-gamma- and Fas/APO-1-induced death. Pepstatin A, an inhibitor of cathepsin D, suppressed cell death in these systems and interfered with the TNF-alpha-induced programmed cell death of U937 cells as well. During cell death, expression of cathepsin D was elevated and processing of the protein was affected, which resulted in high steady-state levels of an intermediate, proteolytically active, single chain form of this protease. Overexpression of cathepsin D by ectopic expression induced cell death in the absence of any external stimulus. Altogether, these results suggest that this well-known endoprotease plays an active role in cytokine-induced programmed cell death, thus adding cathepsin D to the growing list of proteases that function as positive mediators of apoptosis.

Language of Publication

English

Unique Identifier

96324394

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MeSH Heading (Major)

Antigens, CD95|*PD; Apoptosis|*; Cathepsin D|GE/*ME; Interferon Type II|*PD; Tumor Necrosis Factor|*PD

MeSH Heading

Cell Survival; DNA, Antisense|ME; Hela Cells; Human; Pepstatins|ME; RNA|ME; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0261-4189

Country of Publication

ENGLAND

Record 61 from database: MEDLINE
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Title

Monoclonal antibody toward lysosomal cathepsin B cross-reacts preferentially with distinct histone classes.

Author

Seeler BJ; Horton MJ; Szego CM; DeLange RJ

Address

Department of Biology, University of California, Los Angeles 90024.

Source

Int J Biochem, 1988, 20:10, 1089-106

Abstract

1. A set of monoclonal antibodies (Mab) was prepared against cathepsin B (CB) from rat preputial-gland, an organ characterized by rapidly-renewing cell populations, which is a uniquely enriched source of lysosomal enzymes, including CB. Minute amounts of CB are known to be transferred abruptly to the nuclear compartment in a variety of activated cells. 2. Since, on the basis of its stringent substrate requirements, CB was expected to function at limited protein loci in chromatin, Mab Line II-B4 was used to probe Western blots of chromatin fractions and selected proteins. 3. The Mab, which was not directed against the active site of CB, cross-reacted preferentially with histones 3 and 4 (H3 and H4) in acid-soluble fractions of chromatin from rat preputial-gland. Line II-B4 also recognized H3 and H4 selectively in calf thymus histones and among histones purified from a wide range of sources from yeast to man. HMG 1 was minimally immunoreactive among preputial gland constituents and carbonic anhydrase (CA) was also sensitive to the Mab. 4. The common determinants were not shared by any of the H1 series, nor by H2A, H2B, protein A24 or a wide range of natural and synthetic products. 5. Origin of the antigenicity was traced by chemical modifications of H3, H4 and CA to the critical contribution of arginine and hydrophobic amino acid residues in its immediate environment, indicating that Line II-B4 may be directed against an epitope comprising the specific binding-site of CB and its selective substrate(s). 6. These data suggest that certain highly conserved cellular constituents may be uniquely vulnerable to limited proteolysis in preproliferative cells responding to mitotic signals.

Language of Publication

English

Unique Identifier

89252386

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MeSH Heading (Major)

Antibodies, Monoclonal|*IM; Cathepsin B|AN/*IM; Histones|*IM; Lysosomes|*EN/IM

MeSH Heading

Animal; Antibody Formation; Carbonate Dehydratase|AN/IM; Cattle; Chromatin|AN/IM; Clitoris|EN; Cross Reactions; Electrophoresis, Polyacrylamide Gel|MT; Epitopes|AN; Female; Rats; Rats, Inbred Strains; Species Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; Thymus Gland|EN

Publication Type

JOURNAL ARTICLE

ISSN

0020-711X

Country of Publication

ENGLAND

Record 62 from database: MEDLINE
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Title

Negative regulation of epidermal growth factor signaling by selective proteolytic mechanisms in the endosome mediated by cathepsin B.

Author

Authier F; Métioui M; Bell AW; Mort JS

Address

INSERM U510, FacultÆe de Pharmacie Paris XI, 5 rue Jean-Baptiste ClÆement, 92296 ChÈatenay-Malabry, France. francois.authier@cep.u-psud.fr

Source

J Biol Chem, 1999 Nov, 274:47, 33723-31

Abstract

We have investigated the relevant protease activity in rat liver, which is responsible for most of the receptor-mediated epidermal growth factor (EGF) degradation in vivo. EGF was sequentially cleaved by endosomal proteases at a limited number of sites, which were identified by high performance liquid chromatography and mass spectrometry. EGF proteolysis is initiated by hydrolysis at the C-terminal Glu(51)-Leu(52) bond. Three additional minor cleavage sites were identified at positions Arg(48)-Trp(49), Trp(49)-Trp(50), and Trp(50)-Glu(51) after prolonged incubation. Using nondenaturating immunoprecipitation and cross-linking procedures, the major proteolytic activity was identified as that of the cysteine protease cathepsin-B. The effect of injected EGF on subsequent endosomal EGF receptor (EGFR) proteolysis was further evaluated by immunoblotting. Using endosomal fractions prepared from EGF-injected rats and incubated in vitro, the EGFR was lost with a time course superimposable with the loss of phosphotyrosine content. The cathepsin-B proinhibitor CA074-Me inhibited both in vivo and in vitro the endosomal degradation of the EGFR and increased the tyrosine phosphorylation states of the EGFR protein and the molecule SHC within endosomes. The data, therefore, describe a unique pathway for the endosomal processing of internalized EGF receptor complexes, which involves the sequential function of cathepsin-B through selective degradation of both the ligand and receptor.

Language of Publication

English

Unique Identifier

20026911

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MeSH Heading (Major)

Cathepsin B|*ME; Endosomes|*ME; Epidermal Growth Factor|*ME; Signal Transduction|*

MeSH Heading

Amino Acid Sequence; Animal; Catalysis; Endocytosis; Hydrolysis; Iodine Radioisotopes; Liver|ME; Male; Rats; Rats, Sprague-Dawley; Receptor, Epidermal Growth Factor|ME; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 63 from database: MEDLINE
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Title

Inflammation-related neutrophil proteases, cathepsin G and elastase, function as insulin-like growth factor binding protein proteases.

Author

Gibson TL; Cohen P

Address

Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Source

Growth Horm IGF Res, 1999 Aug, 9:4, 241-53

Abstract

Over the past few years, several proteolytic enzymes have been identified as insulin-like growth factor binding protein (IGFBP) proteases. It has been suggested that proteolytic cleavage of IGFBPs is associated with regulation of the proliferative effects of IGFs on their target cells. In this study, we have demonstrated that two neutrophil proteases, cathepsin G and elastase, effectively cleave IGFBPs in vitro and in vivo at concentrations lower than previous described IGFBP proteases. Purified leukocyte cathepsin G and elastase cleaved all six well-characterized IGFBPs into distinct fragments in a concentration-dependent manner. Under similar experimental conditions, cathepsin G preferentially cleaved IGFBP-5, followed by BP-2, BP-3, BP-4, BP-1, and BP-6. In comparison, elastase equally preferred IGFBP-3 and IGFBP-4, followed by BP-1, BP-5, BP-6, and BP-2. Proteolysis of rh(125)I-IGFBP-3 by cathepsin G was blocked by alpha(1)-antichymotrypsin, while elastase proteolytic activity was blocked by alpha(1)-proteinase inhibitor as expected. Elastase, but not cathepsin G, cleaved free IGF-I into a smaller molecular weight fragment in vitro, possibly designating unique functions for each protease within the IGF axis. Sequence analysis of IGFBP-3 fragments produced by cathepsin G and elastase demonstrated that each protease cleaved IGFBP-3 at unique sites within its midregion. More importantly, extracts from purified neutrophils have demonstrated significant proteolytic cleavage of IGFBP-3 that resembles elastase proteolysis of IGFBP-3. Recent studies using a monocyte-like cell model have also shown significant cleavage of IGFBP-3. These in vitro and in vivo data suggest that the neutrophil proteases, cathepsin G and elastase, in addition to their previously described functions as extracellular matrix-degrading enzymes, may potentially act as IGFBP proteases involved in regulation of IGFs and IGFBPs during inflammation and wound healing. Copyright 1999 Harcourt Publishers Ltd.

Language of Publication

English

Unique Identifier

99444069

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MeSH Heading (Major)

Cathepsins|AI/*ME; Inflammation|*ME; Insulin-Like Growth-Factor-Binding Proteins|*ME; Neutrophils|*ME; Pancreatic Elastase|AI/*ME

MeSH Heading

alpha 1-Antichymotrypsin|PD; Cells, Cultured; Culture Media, Conditioned; Human; Immunoblotting; Insulin-Like Growth Factor Binding Protein 3|ME; Insulin-Like Growth Factor I|ME; Insulin-Like Growth Factor-Binding Protein 2|ME; Insulin-Like Growth-Factor Binding Protein 1|ME; Insulin-Like Growth-Factor-Binding-Protein 5|ME; Peptide Fragments|AN/ME; Phenylmethylsulfonyl Fluoride|PD; Protease Inhibitors|PD; Sequence Analysis, Protein; Support, U.S. Gov't, P.H.S.; Trypsin Inhibitor, Bowman-Birk Soybean|PD

Publication Type

JOURNAL ARTICLE

ISSN

1096-6374

Country of Publication

SCOTLAND

Record 64 from database: MEDLINE
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Title

Characterization and properties of two monoclonal antibodies specific for the Mr 52,000 precursor of cathepsin D in human breast cancer cells.

Author

Freiss G; Vignon F; Rochefort H

Address

INSERM U 148, UnitÆe Hormones et Cancer, Montpellier, France.

Source

Cancer Res, 1988 Jul, 48:13, 3709-15

Abstract

The Mr 52,000 estrogen-induced protein secreted by MCF7 cells has been identified as a procathepsin D (procath D), which increases cell growth in vitro, may stimulate invasiveness by digesting extracellular matrix and appears to be a tissue marker for predicting relapses in breast cancer patients. The protease is also present within mammary cells as Mr 48,000, 34,000, 14,000 mature forms that were also recognized by the previously described antibodies to the Mr 52,000 protein (M. Garcia, F. Capony, D. Derocq, D. Simon, B. Pau, and H. Rochefort, Cancer Res., 45: 709-716, 1985). Using selective screening with a [35S]methionine-labeled MCF7 cell lysate, we have now isolated two new monoclonal antibodies interacting exclusively with the Mr 52,000 procath D. The two monoclonal antibodies, M2E8* and D9H8*, purified from ascitic fluids are IgG1. Their respective Kds for Mr 52,000 procath D are 0.96 and 0.18 nM. They are directed against two separate domains of the proenzyme that differ from the three domains of previously described antibodies. They both interact with the deglycosylated protein and recognize the autoactivated secreted proenzyme (Mr 51,000), which is devoid of the first part of the NH2-terminal end. By immunodetection of cathepsin D proteolytic activity in plasma, these two antibodies were found to recognize selectively human cathepsin D but not the cathepsin D of other species (rat, mouse, rabbit, goat, and horse) whereas antibodies to mature cathepsin D were less species specific. Using sequential passages on concanavalin A-Sepharose and Sepharose matrices coupled to antibodies to the precursor and antibodies to the mature cathepsin D, we separately purified to homogeneity the Mr 52,000 procath D form and its processed cellular forms, whose biological activities can now be assessed independently. The two monoclonal antibodies were also shown to inhibit the uptake and processing of the Mr 52,000 cathepsin D in MCF7 cells (mostly D9H8*) and to decrease its proteolytic activity, mostly on extracellular matrix (M2E8*). These two monoclonal antibodies are therefore new tools for studying the function, regulation, cellular processing, and localization of procath D as well as the clinical significance of its concentration in normal and tumoral mammary epithelial cells.

Language of Publication

English

Unique Identifier

88241564

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MeSH Heading (Major)

Antibodies, Monoclonal|*IM; Breast Neoplasms|EN/*IM; Cathepsin D|*IM/IP; Enzyme Precursors|*IM/IP

MeSH Heading

Antibody Specificity; Antigen-Antibody Reactions; Biological Transport; Epitopes; Glycoproteins|IM; Human; Molecular Weight; Protein Processing, Post-Translational; Species Specificity; Support, Non-U.S. Gov't; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0008-5472

Country of Publication

UNITED STATES

Record 65 from database: MEDLINE
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Title

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis [see comments]

Author

Toomes C; James J; Wood AJ; Wu CL; McCormick D; Lench N; Hewitt C; Moynihan L; Roberts E; Woods CG; Markham A; Wong M; Widmer R; Ghaffar KA; Pemberton M; Hussein IR; Temtamy SA; Davies R; Read AP; Sloan P; Dixon MJ; Thakker NS

Address

Department of Medical Genetics, St. Mary's Hospital, Manchester, UK.

Source

Nat Genet, 1999 Dec, 23:4, 421-4

Abstract

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Language of Publication

English

Unique Identifier

20047769

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MeSH Heading (Major)

Dipeptidyl Peptidase I|*DF/*GE; Papillon-Lefevre Disease|*EN/*GE/PA; Periodontitis, Juvenile|*EN/*GE/PA; Point Mutation|*

MeSH Heading

Base Sequence; Chromosomes, Human, Pair 11|GE; DNA Primers|GE; DNA, Complementary|GE; Exons; Female; Genes, Recessive; Human; Introns; Linkage (Genetics); Male; Microsatellite Repeats; Pedigree; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

1061-4036

Country of Publication

UNITED STATES

Record 66 from database: MEDLINE
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Title

Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization.

Author

Gowen M; Lazner F; Dodds R; Kapadia R; Feild J; Tavaria M; Bertoncello I; Drake F; Zavarselk S; Tellis I; Hertzog P; Debouck C; Kola I

Address

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.

Source

J Bone Miner Res, 1999 Oct, 14:10, 1654-63

Abstract

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.

Language of Publication

English

Unique Identifier

99421464

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MeSH Heading (Major)

Bone Density|*PH; Bone Matrix|*ME; Cathepsins|*GE; Osteopetrosis|*GE

MeSH Heading

Animal; Comparative Study; Growth Plate|PH; Mice; Mice, Knockout; Splenomegaly|GE; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0884-0431

Country of Publication

UNITED STATES

Record 67 from database: MEDLINE
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Title

Cathepsin J, a novel murine cysteine protease of the papain family with a placenta-restricted expression.

Author

Tisljar K; Deussing J; Peters C

Address

Medizinische Molekularbiologie, Abteilung HÂamatologie-Onkologie, Klinikum der Albert-Ludwigs-UniversitÂat Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

Source

FEBS Lett, 1999 Oct, 459:3, 299-304

Abstract

A novel mouse cysteine protease of the papain family was identified by searching the dbEST database. A 1.28 kb full-length cDNA was obtained which contains an open reading frame of 999 nucleotides and encodes a predicted polypeptide of 333 amino acids. The deduced polypeptide exhibits features characteristic of cysteine proteases of the papain type including the highly conserved residues of the catalytic triad, and was hence named cathepsin J. Cathepsin J represents the murine homologue of a previously described rat cathepsin L-related protein. Mature cathepsin J shows 59.3% identity to mouse cathepsin L and contains the characteristic ER(F/W)NIN motif within the propeptide indicating that this protease belongs to the subgroup of cathepsin L-like cysteine proteases. Northern blot analysis of various tissues revealed a placenta-restricted expression. This expression pattern may suggest a role of cathepsin J in embryo implantation and/or placental function. Ctsj was mapped to mouse chromosome 13 in the vicinity of cathepsin L suggesting that cathepsin J may have arisen by gene duplication from cathepsin L or a common ancestral gene.

Language of Publication

English

Unique Identifier

99456833

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MeSH Heading (Major)

Cathepsins|BI/*GE/ME; Placenta|*EN/ME

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Chromosome Mapping; Cysteine Endopeptidases|BI/GE/ME; DNA, Complementary|AN; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Papain|CH/CL; Sequence Homology, Amino Acid; Support, Non-U.S. Gov't; Tissue Distribution

Publication Type

JOURNAL ARTICLE

ISSN

0014-5793

Country of Publication

NETHERLANDS

Record 68 from database: MEDLINE
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Title

Immunocytochemical localization of cathepsin D in lysosomes of cortical collecting tubule cells of the rat kidney.

Author

Yokota S; Tsuji H; Kato K

Address

 

Source

J Histochem Cytochem, 1985 Mar, 33:3, 191-200

Abstract

Immunocytochemical localization of cathepsin D in rat renal tubules was investigated by means of indirect immunoenzyme and protein A--gold techniques. By light microscopy, fine granular staining was seen in the mesangial cells of glomeruli. Heavy reaction deposits were present in the cortical tubular segments and some of the medullary collecting tubules. The proximal tubules contained a few positive granules. Other segments were negative for cathepsin D. By electron microscopy, gold particles representing the antigenic sites for cathepsin D were present in cytoplasmic granules and multivesicular bodies of the segment of the cortical collecting tubule. These cytoplasmic granules were presumed to be digestive vacuoles (secondary lysosomes) from their morphological profile. The proximal tubule cells contained the very weakly labeled secondary lysosomes. No specific labeling was noted in other segments of the nephron. Control experiments confirmed the specificity of the immunostaining. Quantitative analysis of the labeling density in each subcellular compartment also confirmed that the main subcellular sites for cathepsin D are the secondary lysosomes and multivesicular bodies. The labeling density in these granules of the lysosomal system varied widely with the individual granules, suggesting that there is a considerable heterogeneity of enzyme content among the granules of the lysosomal system. The prominent presence of cathepsin D in the cortical collecting tubule suggests a certain segment-specific function of this proteinase.

Language of Publication

English

Unique Identifier

85132545

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MeSH Heading (Major)

Cathepsin D|*AN; Kidney Tubules|*EN; Kidney Tubules, Collecting|*EN/UL; Lysosomes|*EN

MeSH Heading

Animal; Gold; Histocytochemistry; Immunoenzyme Techniques; Kidney Cortex|EN/UL; Microscopy, Electron|MT; Rats; Rats, Inbred Strains; Staining; Staphylococcal Protein A; Subcellular Fractions|EN; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0022-1554

Country of Publication

UNITED STATES

Record 69 from database: MEDLINE
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Title

Cathepsin B is a prorenin processing enzyme.

Author

Neves FA; Duncan KG; Baxter JD

Address

Metabolic Research Unit, University of California, San Francisco 94143-0540, USA.

Source

Hypertension, 1996 Mar, 27:3 Pt 2, 514-7

Abstract

Conversion of prorenin to renin results from proteolytic cleavage of a 43-amino-acid prorenin prosegment in renal juxtaglomerular cells. The enzyme that performs this processing is not known. Of several enzymes proposed, cathepsin B is a candidate because it colocalizes with renin in juxtaglomerular cell secretory granules and accurately cleaves the prosegment of human prorenin in vitro. It is not known whether cathepsin B can perform this function in the cell. We examined this using secretory granule-containing rat GH4C1 cells transfected with a human preprorenin expression vector. When treated with secretagogue (KCl 50 mmol/L + forskolin 10 micromol/L), these cells secrete 95% prorenin and 5% active renin into the medium, indicating little prorenin processing activity. In contrast, when the cells are cotransfected with a vector that expresses human preprocathepsin B or mouse prohormone convertase 1, secretagogue-induced secretion of active renin increased to 12% and 16.5%, respectively. With antisera that recognize the prosegment and renin, prorenin and renin were identified as proteins of 47 and 43 kD, respectively, and an antibody specific to the prosegment precipitated only the 47-kD species. These results do not address whether cathepsin B is the authentic renal prorenin processing enzyme. However, the results do demonstrate that cathepsin B can localize to the appropriate subcellular compartment and process prorenin to renin in GH4C1 cells and are consistent with a role for this enzyme in prorenin processing.

Language of Publication

English

Unique Identifier

96188974

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MeSH Heading (Major)

Cathepsin B|GE/*ME; Enzyme Precursors|GE/*ME; Protein Processing, Post-Translational|*; Renin|GE/*ME

MeSH Heading

Animal; Cell Line; Gene Transfer; Human; Mice; Rats; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0194-911X

Country of Publication

UNITED STATES

Record 70 from database: MEDLINE
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Title

Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization.

Author

Gowen M; Lazner F; Dodds R; Kapadia R; Feild J; Tavaria M; Bertoncello I; Drake F; Zavarselk S; Tellis I; Hertzog P; Debouck C; Kola I

Address

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.

Source

J Bone Miner Res, 1999 Oct, 14:10, 1654-63

Abstract

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.

Language of Publication

English

Unique Identifier

99421464

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MeSH Heading (Major)

Bone Density|*PH; Bone Matrix|*ME; Cathepsins|*GE; Osteopetrosis|*GE

MeSH Heading

Animal; Comparative Study; Growth Plate|PH; Mice; Mice, Knockout; Splenomegaly|GE; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0884-0431

Country of Publication

UNITED STATES

Record 71 from database: MEDLINE
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Title

Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells.

Author

Cavaillès V; Augereau P; Rochefort H

Address

Institut National de la SantÆe et de la Recherche MÆedicale, U 148, Unit Hormones and Cancer, Montpellier, France.

Source

Proc Natl Acad Sci U S A, 1993 Jan, 90:1, 203-7

Abstract

The cathepsin D (cath-D) gene, coding for a ubiquitous lysosomal aspartyl protease, is overexpressed in aggressive human breast cancers, and its transcription is induced by estrogens in hormone-responsive breast cancer cells. We have determined the structure and function of the proximal 5' upstream region of the human cath-D gene from MCF7 cells. We show that the promoter has a compound structure with features of both housekeeping genes (high G+C content and potential transcription factor Sp1 sites) and regulated genes (TATAA sequence). By RNase protection assay, we show that transcription is initiated at five major transcription sites (TSSI to -V) spanning 52 base pairs. In hormone-responsive breast cancer cells, estradiol increased by 6- to 10-fold the level of RNAs initiated at TSSI, which is located about 28 base pairs downstream from the TATA box. The specific regulation by estradiol of transcription starting at site I exclusively was confirmed by primer extension. Moreover, the same estradiol effect was observed in the ZR75-1 cell line and in MDA-MB231 estrogen-resistant breast cancer cells stably transfected with the estrogen receptor. Site-directed mutagenesis indicated that the TATA box is essential for initiation of cath-D gene transcription at TSSI. In breast cancer biopsy samples, high levels of TATA-dependent transcription were correlated with overexpression of cath-D mRNA. We conclude that cath-D behaves, depending on the conditions, as a housekeeping gene with multiple start sites or as a hormone-regulated gene that can be controlled from its TATA box.

Language of Publication

English

Unique Identifier

93126342

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MeSH Heading (Major)

Breast Neoplasms|*GE; Cathepsin D|*GE; Estradiol|*PD; Gene Expression Regulation, Enzymologic|*; Gene Expression Regulation, Neoplastic|*; Promoter Regions (Genetics)|*; Transcription, Genetic|*/DE; TATA Box|*

MeSH Heading

Animal; Antisense Elements (Genetics); Base Sequence; Comparative Study; DNA|GE/IP; DNA, Neoplasm|GE/IP; Exons; Female; Human; Introns; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Rats; Restriction Mapping; RNA Probes; Sequence Homology, Nucleic Acid; Support, Non-U.S. Gov't; Transfection; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0027-8424

Country of Publication

UNITED STATES

Record 72 from database: MEDLINE
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Title

Neutrophil cathepsin G increases calcium flux and inositol polyphosphate production in cultured endothelial cells.

Author

Peterson MW; Gruenhaupt D; Shasby DM

Address

Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City 52242.

Source

J Immunol, 1989 Jul, 143:2, 609-16

Abstract

Exposure of endothelial cells (ENDO) to human neutrophil cathepsin G (CG) increases albumin flux across the endothelial monolayer. Since calcium influences cell shape and barrier function of ENDO monolayers, the current study was designed to determine if CG acted through alterations in Ca2+ homeostasis in ENDO. The role of Ca2+ in the increased permeability of ENDO monolayers to albumin after exposure to CG was studied by using ENDO monolayers cultured on polycarbonate filters. Exposure of ENDO monolayers to CG in the presence of the Ca2+-antagonist lanthanum partially prevented the increase in albumin flux, but exposure in the presence of agents that block voltage-regulated calcium channels did not block the increase in albumin flux. To monitor the effect of CG on Ca2+-flux, ENDO were labeled with 45Ca2+ and changes in Ca2+ flux were monitored by the release of 45Ca2+. From 1 to 15 minutes after exposure of ENDO to CG, there was increased release of 45Ca2+ compared with control cells. Calcium channel blocking agents did not inhibit the increased release of 45Ca2+, but lanthanum partially blocked the increase. The increased release of Ca2+ appeared to be due, at least in part, to activation of phospholipase C because there was an increase both in inositol polyphosphate species and in diglycerides after incubation of ENDO with CG. These studies support the hypothesis that CG increases the flux of calcium in ENDO, that this increase in Ca2+ flux may result from activation of phospholipase C, and that this system may be involved in the decreased barrier properties of the ENDO after CG exposure.

Language of Publication

English

Unique Identifier

89292684

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MeSH Heading (Major)

Calcium Channels|DE/EN/*PH; Cathepsins|*PH; Endothelium, Vascular|DE/EN/*PH; Neutrophils|DE/*EN/PH

MeSH Heading

Albumins|ME; Animal; Calcium|PH; Calcium Channel Blockers|PD; Calcium Radioisotopes|ME; Cells, Cultured; Extracellular Matrix|PH; Lanthanum|PD; Phospholipase C|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Swine

Publication Type

JOURNAL ARTICLE

ISSN

0022-1767

Country of Publication

UNITED STATES

Record 73 from database: MEDLINE
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Title

Cathepsin J, a novel murine cysteine protease of the papain family with a placenta-restricted expression.

Author

Tisljar K; Deussing J; Peters C

Address

Medizinische Molekularbiologie, Abteilung HÂamatologie-Onkologie, Klinikum der Albert-Ludwigs-UniversitÂat Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

Source

FEBS Lett, 1999 Oct, 459:3, 299-304

Abstract

A novel mouse cysteine protease of the papain family was identified by searching the dbEST database. A 1.28 kb full-length cDNA was obtained which contains an open reading frame of 999 nucleotides and encodes a predicted polypeptide of 333 amino acids. The deduced polypeptide exhibits features characteristic of cysteine proteases of the papain type including the highly conserved residues of the catalytic triad, and was hence named cathepsin J. Cathepsin J represents the murine homologue of a previously described rat cathepsin L-related protein. Mature cathepsin J shows 59.3% identity to mouse cathepsin L and contains the characteristic ER(F/W)NIN motif within the propeptide indicating that this protease belongs to the subgroup of cathepsin L-like cysteine proteases. Northern blot analysis of various tissues revealed a placenta-restricted expression. This expression pattern may suggest a role of cathepsin J in embryo implantation and/or placental function. Ctsj was mapped to mouse chromosome 13 in the vicinity of cathepsin L suggesting that cathepsin J may have arisen by gene duplication from cathepsin L or a common ancestral gene.

Language of Publication

English

Unique Identifier

99456833

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MeSH Heading (Major)

Cathepsins|BI/*GE/ME; Placenta|*EN/ME

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Chromosome Mapping; Cysteine Endopeptidases|BI/GE/ME; DNA, Complementary|AN; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Papain|CH/CL; Sequence Homology, Amino Acid; Support, Non-U.S. Gov't; Tissue Distribution

Publication Type

JOURNAL ARTICLE

ISSN

0014-5793

Country of Publication

NETHERLANDS

Record 74 from database: MEDLINE
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Title

Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E.

Author

Bennett K; Levine T; Ellis JS; Peanasky RJ; Samloff IM; Kay J; Chain BM

Address

Department of Biology, University College London, GB.

Source

Eur J Immunol, 1992 Jun, 22:6, 1519-24

Abstract

Proteolytic degradation (processing) of antigen by antigen-presenting cells is a major regulatory step in the activation of a T lymphocyte immune response. However, the enzymes responsible for antigen processing remain largely undefined. In this study we show that cathepsin E, and not the ubiquitous lysosomal cathepsin D, is the major aspartic proteinase in a murine antigen-presenting cell line, A20. This enzyme is localized to a non-lysosomal compartment of the endosomal system in these cells. Functional studies using a highly specific inhibitor of cathepsin E show that this enzyme is essential for the processing of ovalbumin by this cell line. Thus, cathepsin E, whose function was hitherto unknown, may play a major role in antigen processing.

Language of Publication

English

Unique Identifier

92289810

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MeSH Heading (Major)

Antigen-Presenting Cells|*PH; Cathepsins|*PD; Histocompatibility Antigens Class II|*ME; Ovalbumin|*ME

MeSH Heading

Animal; Aspartic Endopeptidases|AI/AN; B-Lymphocytes|IM; Cell Fractionation; Chromatography, Gel; Dose-Response Relationship, Immunologic; Fluorescent Antibody Technique; Interleukin-2|SE; Macrophages|IM; Mice; Mice, Inbred CBA; Molecular Weight; Pepstatins|PD; Support, Non-U.S. Gov't; T-Lymphocytes|IM

Publication Type

JOURNAL ARTICLE

ISSN

0014-2980

Country of Publication

GERMANY

Record 75 from database: MEDLINE
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Title

Regulation of the expression of mitogen-regulated protein (MRP; proliferin) and cathepsin L in cultured cells and in the murine placenta.

Author

Nilsen Hamilton M; Jang YJ; Delgado M; Shim JK; Bruns K; Chiang CP; Fang Y; Parfett CL; Denhardt DT; Hamilton RT

Address

Department of Biochemistry and Biophysics, Iowa State University, Ames 50011.

Source

Mol Cell Endocrinol, 1991 May, 77:1-3, 115-22

Abstract

The genes encoding mitogen-regulated protein (MRP; also called proliferin; PLF) and procathepsin L (CL; also called major excreted protein; MEP) are expressed to high levels in the mouse placenta. Although they are both regulated by epidermal growth factor (EGF) and fibroblast growth factor (FGF) in 3T3 cells, expression of these genes is differently regulated with growth state. The expression patterns of MRP and CL as a function of murine development are also different. Basal and growth factor-stimulated levels of MRP expression are much higher in growing than in quiescent 3T3 cells, whereas CL levels are similar. These changes in gene expression in cultured quiescent cells parallel the changes in MRP and CL expression observed in the late-gestational quiescent placenta. These results suggest growth factors may regulate the expression of these genes, but other influences also regulate the expression of MRP and CL in vivo.

Language of Publication

English

Unique Identifier

92275171

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MeSH Heading (Major)

Cathepsins|*GE/ME; Gene Expression Regulation|*; Glycoproteins|*GE/ME; Growth Substances|*GE/ME; Placenta|GD/*ME

MeSH Heading

Animal; Cells, Cultured; Epidermal Growth Factor|PD; Fibroblast Growth Factor|PD; Gestational Age; Human; Immunoenzyme Techniques; Mice; RNA, Messenger|ME; Support, U.S. Gov't, P.H.S.; Tetradecanoylphorbol Acetate|PD; Transforming Growth Factor alpha|PD; 3T3 Cells

Publication Type

JOURNAL ARTICLE

ISSN

0303-7207

Country of Publication

NETHERLANDS

Record 76 from database: MEDLINE
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Title

Developmental expression of cathepsin L and c-rasHa in the mouse placenta.

Author

Hamilton RT; Bruns KA; Delgado MA; Shim JK; Fang Y; Denhardt DT; Nilsen Hamilton M

Address

Department of Zoology and Genetics, Iowa State University, Ames 50011-3223.

Source

Mol Reprod Dev, 1991 Dec, 30:4, 285-92

Abstract

An investigation is described of the expression of the cysteine proteinase cathepsin L during placental development. In addition, whether cathepsin L expression is linked to c-rasHa expression in development, as it is in metastatic cells, is examined. Large amounts of cathepsin L and its transcript are present in the mouse placenta, more than six times more than in adult kidney and liver. Throughout gestation, cathepsin L and its transcript are located in the giant cells and spongiotrophoblasts of the placenta. Several forms of different mobility on denaturing gels are found in the placenta. Their apparent molecular weights, as determined from the gels, are 43,000, 39,000, 29,000, and 20,000. The 39-kDa form is procathepsin L. The 29-kDa and 20-kDa forms are lysosomal cathepsin Ls. The 39-kDa procathepsin L and the 20-kDa mature cathepsin L are the most abundant species in the placenta and are present in about equal amounts throughout gestation. At any time during gestation, placental minces synthesize and secrete only procathepsin L. The amniotic fluid of the fetus contains the 43-kDa form of cathepsin L and procathepsin L, but no detectable amounts of mature cathepsin L. By contrast, serum from nonpregnant or pregnant mice contains three forms of cathepsin L (i.e., the 43-kDa form, procathepsin L, and mature cathepsin L). Cathepsin L and the rasHa oncogene are expressed in two coincident waves corresponding to periods during which the placenta is invasive and just before parturition. The presence of large amounts of cathepsin L in the placenta suggests that the proteinase has a significant function there. Expression of cathepsin L in the placenta is potentially under the control of the ras gene product p21; both are under developmental control.

Language of Publication

English

Unique Identifier

92088530

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MeSH Heading (Major)

Cathepsins|*BI/GE/SE; Cysteine Endopeptidases|*BI/GE/SE; Placenta|*ME/SE; Proto-Oncogene Protein p21(ras)|*BI/GE/ME

MeSH Heading

Animal; Blotting, Northern; Blotting, Western; Cell Division; Cell Transformation, Neoplastic; Female; Gene Expression Regulation; Genes, ras; Glyceraldehyde-3-Phosphate Dehydrogenases|ME; Immunoblotting; Immunohistochemistry; Kidney|ME; Liver|ME; Mice; Precipitin Tests; Pregnancy; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Time Factors

Publication Type

JOURNAL ARTICLE

ISSN

1040-452X

Country of Publication

UNITED STATES

Record 77 from database: MEDLINE
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Title

Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation.

Author

Ioachim E; Kamina S; Demou A; Kontostolis M; Lolis D; Agnantis NJ

Address

Pathology Department, Medical School, University of Ioannina, Greece.

Source

Anticancer Res, 1999 May, 19:3A, 2133-9

Abstract

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.

Language of Publication

English

Unique Identifier

99399147

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MeSH Heading (Major)

Breast Neoplasms|*CH/PA/UL; Carcinoma, Infiltrating Duct|*CH/PA/UL; Carcinoma, Lobular|*CH/PA/UL; Metallothionein|*AN; Neoplasm Proteins|*AN

MeSH Heading

Adult; Aged; Carcinoma, Intraductal, Noninfiltrating|CH/PA/UL; Cathepsin D|AN; Cell Division; Comparative Study; Extracellular Matrix Proteins|AN; Female; Frozen Sections; Human; Immunoenzyme Techniques; Ki-67 Antigen|AN; Middle Age; Proliferating Cell Nuclear Antigen|AN; Protein p53|AN; Receptor, erbB-2|AN; Receptor, Epidermal Growth Factor|AN; Receptors, Estrogen|AN; Receptors, Progesterone|AN; Retinoblastoma Protein|AN; Stromelysin 1|AN; Subcellular Fractions|CH

Publication Type

JOURNAL ARTICLE

ISSN

0250-7005

Country of Publication

GREECE

Record 78 from database: MEDLINE
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Title

Human cathepsin G lacking functional glycosylation site is proteolytically processed and targeted for storage in granules after transfection to the rat basophilic/mast cell line RBL or the murine myeloid cell line 32D.

Author

Garwicz D; Lindmark A; Gullberg U

Address

Department of Medicine, Lund University, Sweden.

Source

J Biol Chem, 1995 Nov, 270:47, 28413-8

Abstract

The neutral protease cathepsin G belongs to a family of hematopoietic serine proteases stored in the azurophil granules of the neutrophil granulocyte. To investigate the function of asparagine-linked carbohydrates in neutrophil serine proteases, we constructed a mutant cDNA, coding for human cathepsin G deficient of a functional glycosylation site, for use in a transgenic cellular model. Wild type and mutant cDNA were stably expressed in the rat basophilic/mast cell line RBL and in the murine myeloblast-like cell line 32D. Biosynthetic labeling, followed by immunoprecipitation, SDS-polyacrylamide gel electrophoresis, and fluorography, showed that carbohydrate-deficient cathepsin G was synthesized as a 29-kDa proform in both cell lines. The proform was proteolytically processed into a stable form with an apparent molecular mass of 27.5 kDa, indicating removal of the carboxyl-terminal prodomain. The mutant cathepsin G was enzymatically activated as determined by acquisition of affinity to aprotinin, a serine protease inhibitor. As for wild type cathepsin G, small amounts of the unprocessed form of the mutated enzyme were released from the cells, while the major part was transferred to a granular compartment as demonstrated by subcellular fractionation. Thus, neither processing leading to enzymatic activation nor granular sorting was obviously affected by the lack of oligosaccharides on the mutant cathepsin G. Our results therefore indicate that glycosylation is not essential for these processes. In addition to the previously utilized cell line RBL, we propose the 32D cell line as a suitable cellular model for transgenic expression of human neutrophil serine proteases.

Language of Publication

English

Unique Identifier

96081888

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MeSH Heading (Major)

Cathepsins|*BI/IP; Cytoplasmic Granules|*ME; Protein Processing, Post-Translational|*; Sequence Deletion|*; Transfection|*

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Cell Line; Chromatography, Affinity; DNA Primers; Glutamine; Glycosylation; Human; Kinetics; Leukemia, Basophilic, Acute; Mast Cells; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Point Mutation; Polymerase Chain Reaction; Rats; Recombinant Proteins|BI/IP; Support, Non-U.S. Gov't; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 79 from database: MEDLINE
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Title

Stable expression of protective protein/cathepsin A-green fluorescent protein fusion genes in a fibroblastic cell line from a galactosialidosis patient. Model system for revealing the intracellular transport of normal and mutated lysosomal enzymes.

Author

Naganawa Y; Itoh K; Shimmoto M; Kamei S; Takiguchi K; Doi H; Sakuraba H

Address

Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Honkomagome 3-18-22, Bunkyo-ku, Tokyo 113-8613, Japan.

Source

Biochem J, 1999 Jun, 340 ( Pt 2):, 467-74

Abstract

Fibroblastic cell lines derived from a galactosialidosis patient, stably expressing the chimaeric green fluorescent protein variant (EGFP) gene fused to the wild-type and mutant human lysosomal protective protein/cathepsin A (PPCA) cDNA, were first established as a model system for revealing the sorting and processing of lysosomal enzymes and for investigating the molecular bases of their deficiencies. In the cell line expressing the wild-type PPCA-EGFP chimaera gene (EGFP-PPwild), an 81 kDa form (27 kDa EGFP fused to the C-terminus of the 54 kDa PPCA precursor) was produced, then processed into the mature 32/20 kDa two-chain form free of the EGFP domain. The intracellular cathepsin A, alpha-N-acetylneuraminidase and beta-galactosidase activities, which are deficient in the parent fibroblastic cells, could also be significantly restored in the cells. In contrast with the uniform and strong fluorescence throughout the cytoplasm and nucleus in the mock-cell line expressing only EGFP cDNA, weak reticular and punctate fluorescence was distributed throughout the EGFP-PPwild cell line. Bafilomycin A1, a potent inhibitor of vacuolar ATPase and intracellular acidification, induced the distribution of Golgi-like perinuclear fluorescence throughout the living and fixed cells, in which only the 81 kDa product was detected. After removal of the agent, time-dependent transport of the chimaeric protein from the Golgi apparatus to the prelysosomal structure in living cells was monitored with a confocal laser scanning microscope system. Leupeptin caused the distribution of lysosome-like granular fluorescence throughout the cytoplasm in the fixed cells, although it was hardly observed in living cells. The latter agent also dose-dependently induced an increase in the intracellular amount of the 81 kDa product containing the EGFP domain and inhibited the restoration of cathepsin A activity in the EGFP-PPwild cells after the removal of bafilomycin A1. In parallel, both the mature two-chain form and PPCA function disappeared. These results suggested that the chimaera gene product was transported to acidic compartments (endosomes/lysosomes), where proteolytic processing of the PPCA precursor/zymogen, quenching of the fluorescence, and random degradation of the EGFP portion occurred. A cell line stably expressing a chimaeric gene with a mutant PPCA cDNA containing an A1184-->G (Y395C) mutation, commonly detected in Japanese severe early-infantile type of galactosialidosis patients, showed an endoplasmic reticulum (ER)-like reticular fluorescence pattern. The PPCA-immunoreactive gene product was hardly detected in this cell line. The mutant chimaeric product was suggested to be degraded rapidly in the ER before transport to post-ER compartments. A cell line expressing the chimaeric gene with a T746-->A (Y249N) PPCA mutation exhibited both ER-like reticular and granular fluorescence on the reticular structure that was stronger than that in the EGFP-PPwild cells. Some of them contained large fluorescent inclusion-body-like structures. The ineffectiveness of transport inhibitors in the distribution changes in the two mutant chimaeric proteins suggested that they were not delivered to acidic compartments. Therefore this expression system can possibly be applied to the direct analysis of the sorting defects of mutant gene products in living cells and will be useful for the molecular investigation of lysosomal diseases, including galactosialidosis.

Language of Publication

English

Unique Identifier

99267321

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MeSH Heading (Major)

Carboxypeptidases|*GE; Luminescent Proteins|*GE; Lysosomal Storage Diseases|GE/*ME; Lysosomes|*EN; Recombinant Fusion Proteins|GE/*ME

MeSH Heading

Amino Acid Sequence; Antibiotics, Macrolide|PD; Base Sequence; Biological Transport; Cell Line; DNA, Complementary; Fibroblasts|ME; Human; Leupeptins|PD; Microscopy, Fluorescence; Models, Biological; Molecular Sequence Data; Mutation; Protein Processing, Post-Translational; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0264-6021

Country of Publication

ENGLAND

Record 80 from database: MEDLINE
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Title

Inhibitory effect of thiols on the degradation of albumin by human spleen cathepsin D.

Author

Ikeda K; Koseki T; Suzuki H; Nakagawa S

Address

Department of Applied Biological Science, Nihon University, College of Agriculture and Veterinary Medicine, Kanagawa, Japan.

Source

Biochem Int, 1990, 21:2, 341-7

Abstract

The degradation of native albumin by human spleen cathepsin D was inhibited by GSH, cysteine and cysteamine. The thiols existing physiologically also inhibited reduced-carboxymethylated albumin, indicating that these thiols react preferentially with the enzyme itself rather than the substrate. The inhibitions of native albumin proteolysis were dose-dependent. These effects of thiols which have not been observed in other animal cathepsin D, suggest an essential function for cathepsin D in the human spleen.

Language of Publication

English

Unique Identifier

90386686

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MeSH Heading (Major)

Albumins|*ME; Cathepsin D|*ME; Spleen|*EN; Sulfhydryl Compounds|*PD

MeSH Heading

Cysteamine|ME/PD; Cysteine|ME/PD; Dose-Response Relationship, Drug; Glutathione|ME/PD; Hemoglobins|ME; Human; Hydrogen-Ion Concentration; Substrate Specificity

Publication Type

JOURNAL ARTICLE

ISSN

0158-5231

Country of Publication

AUSTRALIA

Record 81 from database: MEDLINE
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Title

Human cathepsin F. Molecular cloning, functional expression, tissue localization, and enzymatic characterization.

Author

Wang B; Shi GP; Yao PM; Li Z; Chapman HA; Brömme D

Address

Department of Human Genetics, Mount Sinai School of Medicine, CUNY, New York, New York 10029, USA.

Source

J Biol Chem, 1998 Nov, 273:48, 32000-8

Abstract

A cDNA for a novel human papain-like cysteine protease, designated cathepsin F, has been cloned from a lambdagt10-skeletal muscle cDNA library. The nucleotide sequence encoded a polypeptide of 302 amino acids composed of an 88-residue propeptide and a 214-residue mature protein. Protein sequence comparisons revealed 58% homology with cathepsin W; about 42-43% with cathepsins L, K, S, H, and O; and 38% with cathepsin B. Sequence comparisons of the propeptides indicated that cathepsin F and cathepsin W may form a new cathepsin subgroup. Northern blot analysis showed high expression levels in heart, skeletal muscle, brain, testis, and ovary; moderate levels in prostate, placenta, liver, and colon; and no detectable expression in peripheral leukocytes and thymus. The precursor polypeptide of human recombinant cathepsin F, produced in Pichia pastoris, was processed to its active mature form autocatalytically or by incubation with pepsin. Mature cathepsin F was highly active with comparable specific activities toward synthetic substrates as reported for cathepsin L. The protease had a broad pH optimum between 5.2 and 6.8. Similar to cathepsin L, its pH stability at cytosolic pH (7.2) was short, with a half-life of approximately 2 min. This may suggest a function in an acidic cellular compartment. Transient expression of T7-tagged cathepsin F in COS-7 cells revealed a vesicular distribution of the gene product in the juxtanuclear region of the cells. However, contrary to all known cathepsins, the open reading frame of the cathepsin F cDNA did not encode a signal sequence, thus suggesting that the protease is targeted to the lysosomal compartment via an N-terminal signal peptide-independent lysosomal targeting pathway.

Language of Publication

English

Unique Identifier

99041967

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MeSH Heading (Major)

Cathepsins|BI/*CH/GE/*ME; Muscle, Skeletal|*EN

MeSH Heading

Amino Acid Sequence; Base Sequence; Cloning, Molecular; Cysteine Endopeptidases|CH; DNA, Complementary; Female; Gene Library; Human; Hydrogen-Ion Concentration; Kinetics; Male; Molecular Sequence Data; Organ Specificity; Polymerase Chain Reaction; Pregnancy; Recombinant Proteins|BI/CH/ME; Restriction Mapping; Sequence Alignment; Sequence Homology, Amino Acid; Substrate Specificity; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Transcription, Genetic

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 82 from database: MEDLINE
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Title

Augmented inflammatory responses and altered wound healing in cathepsin G-deficient mice.

Author

Abbott RE; Corral CJ; MacIvor DM; Lin X; Ley TJ; Mustoe TA

Address

Division of Plastic and Reconstructive Surgery, Northwestern University Medical School, Chicago, Ill 60611, USA.

Source

Arch Surg, 1998 Sep, 133:9, 1002-6

Abstract

BACKGROUND: Cathepsin G is a neutral serine proteinase that exists primarily in azurophilic granules of neutrophils, but also as a proteolytically active membrane-bound form. While the specificity and many in vitro biological activities have been described for cathepsin G, little is known about the role of this enzyme in neutrophil function in vivo, particularly as it applies to the wound-healing process. OBJECTIVE: To determine the role of cathepsin G in cutaneous tissue repair by examination of full-thickness incisional wound healing in mice with a null mutation for cathepsin G. METHODS: Paired, full-thickness linear incisions were made on the backs of cathepsin G +/+ and cathepsin G -/- mice, and wound tissue was harvested at days 1, 2, 3, 5, 7, 10, and 14 after wounding. Neutrophil influx, myeloperoxidase activity, and migration were examined using light microscopy, the myeloperoxidase assay, and modified Boyden chamber technique, respectively. Wound-breaking strength was measured using tensiometry. RESULTS: The absence of cathepsin G led to a 42% decrease in wound-breaking strength at day 7 after wounding (n=28; P<.002), which returned to the level of control mice by day 10 after wounding. Wound tissue sections in mice lacking cathepsin G also showed a 26% increase in neutrophil myeloperoxidase activity (n=12; P=.001) and an 18% increase in neutrophil influx (n=14; P=.002) at day 3 after wounding. Wound fluid collected on day 5 after wounding from cathepsin G-deficient mice attracted 58% more neutrophils than wound fluid collected from control mice (n=4; P<.05). CONCLUSIONS: Neutrophil cathepsin G is important during the early inflammatory stage of wound healing. Cathepsin G may be involved in processing 1 (or more) soluble mediator(s) in the wound milieu that is responsible for neutrophil chemotaxis. Our findings suggest that tight regulation of inflammation is necessary to prevent impaired healing during early tissue repair.

Language of Publication

English

Unique Identifier

98420285

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MeSH Heading (Major)

Cathepsins|*DF; Inflammation|*EN/IM; Serine Endopeptidases|*DF; Wound Healing|IM/*PH

MeSH Heading

Animal; Mice; Neutrophils|EN/IM; Peroxidase|ME; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0004-0010

Country of Publication

UNITED STATES

Record 83 from database: MEDLINE
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Title

Peptides derived from human C-reactive protein inhibit the enzymatic activities of human leukocyte elastase and cathepsin G: use of overlapping peptide sequences to identify a unique inhibitor.

Author

Yavin EJ; Fridkin M

Address

Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.

Source

J Pept Res, 1998 Apr, 51:4, 282-9

Abstract

Ten overlapping 15-mer peptides, spanning the entire inner disulfide loop of human C-reactive protein (residues 36-97), were used to isolate a potent inhibitor of the enzymes human leukocyte elastase and human leukocyte cathepsin G, which are associated with chronic inflammatory tissue damage. In contrast to the inability of intact C-reactive protein to inhibit both enzymes, the synthetic peptide E62ILIFWSKDIGYSFT76 inhibited leukocyte elastase (Ki = 0.18 microM) and cathepsin G (Ki = 0.25 microM) at concentrations far lower than the acute-phase concentration of C-reactive protein. Several peptide-enzyme binding motifs were elucidated by structure-function studies, with the Glu62 residue being crucial in establishing long-range subsite interactions. Peptides derived from C-reactive protein, which may be generated in vivo by neutrophil-mediated proteolysis as part of a complex regulatory homeostatic mechanism, may play an important role in regulating the activity of matrix-degrading enzymes, specifically at sites of inflammation. The present results thus may shed additional insight on the physiological functions of the major acute-phase reactant C-reactive protein, and perhaps be used as a basis for the design of novel therapeutic substances.

Language of Publication

English

Unique Identifier

98218930

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MeSH Heading (Major)

Carrier Proteins|*CH/GE/*PD; Cathepsins|*AI; Enzyme Inhibitors|*CH/*PD; Pancreatic Elastase|*AI; Peptides|*CH/GE/*PD

MeSH Heading

Amino Acid Sequence; Binding Sites|GE; Human; Molecular Sequence Data; Sequence Analysis; Substrate Specificity

Publication Type

JOURNAL ARTICLE

ISSN

1397-002X

Country of Publication

DENMARK

Record 84 from database: MEDLINE
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Title

Activity and deletion analysis of recombinant human cathepsin L expressed in Escherichia coli.

Author

Smith SM; Gottesman MM

Address

Howard Hughes Medical Institute, National Cancer Institute, Bethesda, Maryland 20892.

Source

J Biol Chem, 1989 Dec, 264:34, 20487-95

Abstract

A cDNA clone encoding the human cysteine protease cathepsin L was expressed at high levels in Escherichia coli in a T7 expression system. The insoluble recombinant enzyme was solubilized in urea and refolded at alkaline pH. 38-kDa procathepsin L was purified by gel filtration at pH 8.0, and a 29-kDa form of the enzyme was purified by gel filtration after autoprocessing of the proenzyme at pH 6.5. The kinetic properties of the 29-kDa species of recombinant cathepsin L were similar to those published for the human liver enzyme (Mason, R. W., Green, G. D. J., and Barrett, A.J. (1985) Biochem. J. 226, 233-241), using benzyloxycarbonyl-Phe-Arg-7-(4-methyl)coumarylamide as substrate. However, the stability of the recombinant enzyme, and its pH optimum for this substrate was shifted to a higher pH. Structure-function studies of cathepsin L were performed by constructing mutations in either the propeptide portion or the carboxyl-terminal light chain portion of the protein. These constructions were expressed in the E. coli system, and enzymatic activities were assayed following solubilization, renaturation, and gel filtration chromatography of the mutated proteins. Deletions of increasing size in the propeptide resulted in large proportional losses of activity, indicating that the propeptide is essential for proper enzyme folding and/or processing in this renaturation system. Deletion of part of the light chain containing a disulfide-forming cysteine residue or a single amino acid substitution of alanine for this cysteine residue resulted in almost complete loss of activity. These data suggest that the disulfide bond joining the heavy and light chains of cathepsin L is essential for enzymatic activity.

Language of Publication

English

Unique Identifier

90062183

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MeSH Heading (Major)

Cathepsins|*GE/IP/ME; Chromosome Deletion|*; Escherichia coli|EN/*GE; Gene Expression|*; Genes, Structural|*

MeSH Heading

Amino Acid Sequence; Animal; Chromatography, Gel; Cloning, Molecular|MT; Comparative Study; Human; Kinetics; Molecular Sequence Data; Plasmids; Recombinant Proteins|IP/ME; Restriction Mapping; Sequence Homology, Nucleic Acid; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Ultrafiltration

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 85 from database: MEDLINE
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Title

Carboxyl-terminal prodomain-deleted human leukocyte elastase and cathepsin G are efficiently targeted to granules and enzymatically activated in the rat basophilic/mast cell line RBL.

Author

Gullberg U; Lindmark A; Lindgren G; Persson AM; Nilsson E; Olsson I

Address

Department of Medicine, University of Lund, Sweden.

Source

J Biol Chem, 1995 May, 270:21, 12912-8

Abstract

The hematopoietic neutral serine proteases leukocyte elastase and cathepsin G are synthesized as inactive precursors, but become activated by removal of an amino-terminal dipeptide and are stored in granules. Moreover, the pro forms of elastase and cathepsin G show carboxyl-terminal prodomains of 20 and 11 amino acids, respectively, which are not present in the mature enzymes. To investigate mechanisms of processing, activation, and granular targeting, we have utilized transgenic expression of myeloid serine proteases in the rat basophilic/mast cell line RBL-1 (Gullberg, U., Lindmark, A., Nilsson, E., Persson, A.-M., and Olsson, I. (1994) J. Biol. Chem. 269, 25219-25225). Leukocyte elastase was stably expressed in RBL-1 cells, and the translation products were characterized by biosynthetic labeling followed by immunoprecipitation, SDS-polyacrylamide gel electrophoresis, and fluorography. Processing of a main pro form of 34 kDa into mature 31- and 29-kDa forms was demonstrated. Translocation of mature forms to granule-containing fractions was shown by subcellular fractionation experiments. The processed forms were enzymatically active, judging by the occurrence of amino-terminal processing demonstrated by radiosequence analysis, the acquisition of affinity for the protease inhibitor aprotinin, and the appearance of elastase activity in transfected RBL cells. To investigate the function of the carboxyl-terminal prodomains, deletion mutants of leukocyte elastase and cathepsin G lacking the carboxyl-terminal extension were constructed and transfected into RBL cells. Our results show that as full-length proteins, the deletion mutants were converted to active enzymes and transferred to granules with kinetics similar to that of wild-type enzymes. We conclude that human leukocyte elastase and cathepsin G are converted into enzymatically active forms when expressed in RBL cells and targeted for storage in granules; the carboxyl-terminal prodomains are necessary neither for enzymatic activation nor for targeting to granules in RBL cells.

Language of Publication

English

Unique Identifier

95279438

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MeSH Heading (Major)

Cathepsins|*ME; Cell Compartmentation|*; Cytoplasmic Granules|*ME; Enzyme Precursors|*ME; Leukocytes|*EN; Pancreatopeptidase|*ME; Stem Cells|*ME

MeSH Heading

Amino Acid Sequence; Aprotinin|ME; Base Sequence; Basophils|ME; Biological Transport; Cell Fractionation; Enzyme Activation; Human; Mast Cells|ME; Molecular Sequence Data; Protein Processing, Post-Translational; Recombinant Proteins|ME; Sequence Deletion; Structure-Activity Relationship; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0021-9258

Country of Publication

UNITED STATES

Record 86 from database: MEDLINE
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Title

Stimulation of human lymphocytes by cathepsin G.

Author

Hase Yamazaki T; Aoki Y

Address

Department of Biochemistry and Nutrition, Institute of Public Health, Tokyo, Japan.

Source

Cell Immunol, 1995 Jan, 160:1, 24-32

Abstract

We investigated the effect of cathepsin G, a serine protease in polymorphonuclear granulocytes, on the function of human lymphocytes. Cathepsin G increased the [3H]thymidine incorporation into human lymphocytes. This mitogenic activity was due to the proteolytic activity of cathepsin G. Both B and T cells showed increased [3H]thymidine incorporation, and this effect was more remarkable for T cells than for B cells. Among the T cell subsets, CD4+ T cells showed the increase in DNA synthesis, but CD8+ T cells did not. When human lymphocytes were stimulated with cathepsin G, intracellular free Ca2+ concentration ([Ca2+]i) increased in B and T cells, including CD4+ T cells and CD8+ T cells. The change in intracellular Ca2+ was due to Ca2+ influx and release of intracellular stores. Cathepsin G also induced the production of inositol 1,4,5-trisphosphate (IP3) in B cells, CD4+ T cells, and CD8+ T cells, leading to the release of Ca2+ from intracellular stores. Moreover, the stimulation with cathepsin G resulted in alkalization of the cytosol of B cells, CD4+ T cells, and CD8+ T cells as the result of Na+/H+ antiport activation. The change in intracellular Ca2+, production of IP3, and cytoplasmic alkalization in lymphocytes were due to its proteolytic activity. Cathepsin G released from granulocytes is considered to act on human lymphocytes in vivo and lead to the increase in DNA synthesis of B cells and CD4+ T cells through IP3 production, an increase in [Ca2+]i, and alkalization. However, these second messengers do not lead to the increase in DNA synthesis of CD8+ T cells.

Language of Publication

English

Unique Identifier

95144746

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MeSH Heading (Major)

B-Lymphocytes|*ME; Cathepsins|*PH; T-Lymphocytes|*ME

MeSH Heading

Amino Acid Sequence; Calcium|ME; Cells, Cultured; Fura-2|AA/DU; Human; Hydrogen-Ion Concentration|DE; Inositol 1,4,5-Trisphosphate|BI; Lymphocyte Transformation|DE; Molecular Sequence Data; Support, Non-U.S. Gov't; Terpenes|PD

Publication Type

JOURNAL ARTICLE

ISSN

0008-8749

Country of Publication

UNITED STATES

Record 87 from database: MEDLINE
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Title

Modulation of cathepsin D activity in retinal pigment epithelial cells.

Author

Rakoczy PE; Lai CM; Baines M; Di Grandi S; Fitton JH; Constable IJ

Address

Molecular Biology, Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, 2 Verdun St., Nedlands 6009, WA, Australia.

Source

Biochem J, 1997 Jun, 324 ( Pt 3):, 935-40

Abstract

This project used retinal pigment epithelial (RPE) cells to investigate the effects of up- and down-regulation of cathepsin D expression on the processing of cathepsin D and on the normal phagocytic and digestive function of these cells. RPE cells were transfected with a pHbetaApr-1-neo vector construct carrying the full-length sequence of the translated region of human cathepsin D in sense and antisense directions. Transfected cells were characterized for the presence and expression of the transgene by PCR amplification using transgene-specific primers. Total aspartic proteinase activity present in transformed RPE cells was measured by an enzyme assay using haemoglobin as substrate. Flow cytometry was used to quantify phagocytosis of fluorescein isothiocyanate-labelled rod outer segments (ROS), and lysosomal digestion of ROS was monitored by immunofluorescence. A 435 bp fragment was present in RPE cells carrying the cathepsin D transgene in sense and antisense orientations after PCR amplification. Expression of both 52 kDa procathepsin D and 34 kDa active cathepsin D was significantly up-regulated in sense cathepsin D-transfected RPE cells and down-regulated in RPE cells transfected with antisense cathepsin D. No other forms of cathepsin D were detected in the transfected cells, suggesting that, if pseudo-cathepsin D exists in RPE cells in vivo, it requires the presence of unknown specific regulatory elements. The up- and down-regulation of cathepsin D expression was further confirmed by enzyme assay. Transfected cells retained their phagocytosing ability after ROS challenge and maintained their ability to process ROS. The processing of ROS was significantly slower in RPE cells transfected with antisense than control vector or in sense-cathepsin D-transfected cells. These results demonstrate that cathepsin D is a major proteolytic enzyme participating in the lysosomal digestion of photoreceptor outer segments.

Language of Publication

English

Unique Identifier

97327742

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MeSH Heading (Major)

Cathepsin D|*ME; Pigment Epithelium of Eye|CY/*EN/IM

MeSH Heading

Animal; Aspartic Endopeptidases|ME; Blotting, Western; Cattle; Child; Cloning, Molecular; Genetic Vectors; Human; Phagocytosis; Recombinant Proteins|ME; Rod Outer Segments|ME; RNA, Messenger|GE/ME; Transfection

Publication Type

JOURNAL ARTICLE

ISSN

0264-6021

Country of Publication

ENGLAND

Record 88 from database: MEDLINE
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Title

A unique cathepsin-like protease isolated from CV-1 cells is involved in rapid degradation of retinoblastoma susceptibility gene product, RB, and transcription factor SP1.

Author

Nishinaka T; Fu YH; Chen LI; Yokoyama K; Chiu R

Address

Department of Surgery, School of Medicine, University of California, Los Angeles 90095-1782, USA.

Source

Biochim Biophys Acta, 1997 Apr, 1351:3, 274-86

Abstract

The regulation of transcription factors by kinase or phosphatase has been well-described. However, little is known about the inactivation of transcription factors or the nuclear regulators by proteolytic degradation. In this report, we purified a specific protease, SPase, from nuclear extracts of the green monkey kidney cell line, CV-1. Studies of biochemical characteristics and substrate specificity indicated that SPase is a cathepsin B-like cysteinyl protease. However, the two tryptic peptide sequences derived from the purified SPase are either identical or highly homologous to those of human cathepsin L, and furthermore, SPase shares immunoreactivity with both anti-human cathepsin L and anti-mouse cathepsin L antibody. The SPase was shown to be localized in both cytoplasm and nucleus when subcellular compartments of CV-1 cells were fractionated. Transcription factor, SP1, and retinoblastoma susceptible gene product, RB, are substrates of SPase while other nuclear factors such as c-Jun and c-Fos are not. These results implied that SPase plays an integral role in regulating a set of proteins in the nuclei. In vivo treatment of CV-1 cells with cysteinyl protease inhibitor, E-64d, protected RB from degradation. SPase failed to degrade underphosphorylated RB present in TPA induced terminally differentiated HL-60 or U937 cells. Phosphorylation of RB may cause conformational changes, thus facilitating proteolytic digestion. These observations suggest that an alternative pathway inactivates the function of RB in controlling cell growth. Therefore, a possible role of SPase may be to affect the stability of important regulators involved in controlling cellular proliferation and differentiation.

Language of Publication

English

Unique Identifier

97276898

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MeSH Heading (Major)

Cysteine Endopeptidases|GE/*IP/*ME; Kidney|CY/DE/*EN; Retinoblastoma Protein|CH/GE/*ME; Transcription Factor, Sp1|CH/GE/*ME

MeSH Heading

Amino Acid Sequence; Animal; Blotting, Western; Cathepsins|IM; Cell Division; Cell Extracts|CH; Cells, Cultured; Cysteine Proteinase Inhibitors|PD; Haplorhini; Human; HL-60 Cells|DE; Molecular Sequence Data; Nuclear Proteins|GE/IP/ME; Phosphorylation; Protein Conformation; Substrate Specificity; Support, U.S. Gov't, P.H.S.; Transcription, Genetic

Publication Type

JOURNAL ARTICLE

ISSN

0006-3002

Country of Publication

NETHERLANDS

Record 89 from database: MEDLINE
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Title

Human cathepsin W, a putative cysteine protease predominantly expressed in CD8+ T-lymphocytes.

Author

Linnevers C; Smeekens SP; Brömme D

Address

Arris Pharmaceutical Corp., South San Francisco, CA 94080, USA.

Source

FEBS Lett, 1997 Apr, 405:3, 253-9

Abstract

A 750-bp fragment of a novel human cysteine protease has been identified from the dbEST databank. PCR cloning and DNA sequencing yielded a 1.38-kb full-length cDNA which encodes a polypeptide of 376 amino acids. The protein consists of a putative 21-residue signal peptide, a 106-residue propeptide and a 252-residue mature protein. The deduced amino acid sequence contains the highly conserved residues of the catalytic triad of papain-like cysteine proteases: cysteine, histidine, and asparagine. Furthermore, the protein sequence possesses two potential N-glycosylation sites: one in the propeptide and one in the mature protein. Comparison of the amino acid sequence of human cathepsin W with other human thiol-dependent cathepsins revealed a relatively low degree of similarity (21-31%). In contrast to cathepsins L, S, K, B, H and O, cathepsin W contains a 21-amino acid peptide insertion between the putative active site histidine and asparagine residues and an 8-amino acid C-terminal extension. This unique sequence may indicate that cathepsin W belongs in a novel subgroup of papain-like proteases distinct from that of cathepsin L- and B-like proteases. Northern blot analysis indicates a specific expression of cathepsin W in lymphatic tissues. Further analysis revealed predominant levels of expression in T-lymphocytes, and more specifically in CD8+ cells. The expression of the protease in cytotoxic T-lymphocytes may suggest a specific function in the mechanism or regulation of T-cell cytolytic activity.

Language of Publication

English

Unique Identifier

97261885

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MeSH Heading (Major)

Cathepsins|GE/*ME; Cysteine Endopeptidases|GE/*ME; CD8-Positive T-Lymphocytes|*EN

MeSH Heading

Amino Acid Sequence; Base Sequence; Binding Sites; DNA, Complementary|GE; Gene Expression; Human; Molecular Sequence Data; RNA, Messenger|GE; Sequence Alignment; Sequence Homology, Amino Acid; Tissue Distribution

Publication Type

JOURNAL ARTICLE

ISSN

0014-5793

Country of Publication

NETHERLANDS

Record 90 from database: MEDLINE
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Title

Germinal center B cell apoptosis requires both caspase and cathepsin activity.

Author

van Eijk M; de Groot C

Address

Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.

Source

J Immunol, 1999 Sep, 163:5, 2478-82

Abstract

Follicular dendritic cells (FDCs) select B cells during germinal center (GC) reactions. The B cells that are able to bind to the FDCs receive a signal that leads to the termination of endonuclease activity in the nuclei of those B cells. This signal must be in addition to the signals transferred through the cross-linkage of the B cell receptors and signals resulting from the interactions of the adhesion molecules lymphocyte function-associated Ag-1 and very late Ag-4 with ICAM-1 and VCAM-1, respectively. In this report, we present evidence that the FDCs silence all apoptotic processes in GC B lymphocytes and additionally switch off pre-present endonuclease activity. We also show that GC B cell apoptosis requires cathepsin activity downstream of caspase-3. This cathepsin activity is directly connected to endonuclease activity and therefore may be an interesting target for the antiapoptotic factors produced by FDCs.

Language of Publication

English

Unique Identifier

99384063

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MeSH Heading (Major)

Apoptosis|*IM; B-Lymphocytes|*CY/*EN/IM; Caspases|AI/*ME; Cathepsins|AI/*ME; Germinal Center|*CY/*EN/IM

MeSH Heading

Amino Acid Chloromethyl Ketones|PD; Cells, Cultured; Cysteine Proteinase Inhibitors|PD; Dendritic Cells|IM; Endonucleases|AI/ME; Enzyme Activation|IM; Human; Leucine|AA/PD; Signal Transduction|IM; Tonsil

Publication Type

JOURNAL ARTICLE

ISSN

0022-1767

Country of Publication

UNITED STATES

Record 91 from database: MEDLINE
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Title

The lysosomal enzymes acid phosphatase and cathepsin D in rats intoxicated with Senna occidentalis seeds.

Author

Calore EE; Calore NM; Weg R; Cavaliere MJ; Ruckert da Rosa A; De Souza Dias S

Address

EmÆilio Ribas Institute, Pathology Section, SÃao Paulo, Brazil. calore@sti.com.br

Source

J Submicrosc Cytol Pathol, 1999 Apr, 31:2, 259-64

Abstract

Chronic administration of Senna occidentalis seeds induces an experimental toxic myopathy characterized by skeletal muscle fibers atrophy, decrease in histochemical activity of cytochrome oxidase, and increase of the acid phosphatase activity in muscle fibres at the light microscopic level. The mechanisms that lead to the increase of this lysosomal enzyme activity are not known and could be related to other biochemical disturbs than the mitochondrial function impairment. The main aim of the present study is to localize the acid phosphatase activity using a cytochemical method at transmission electron microscopy level and to quantify cathepsin D in muscle of rats chronically intoxicated with Senna occidentalis seeds by immunoblotting. Acid phosphatase was observed in lysosomes and over profiles of some organelles apparently not involved by lysosomal membrane. In addition immunoblotting demonstrated a decrease in the content of the precursor and of the mature form of cathepsin D in samples of muscles and liver of intoxicated animals. We concluded that there is a selective increase in acid phosphatase activity in muscle--and maybe in other tissues--of animals intoxicated with Senna occidentalis, that can be related to the skeletal muscle atrophy and the intense decrease in weight gain of these animals. Further studies should be performed to establish the mechanisms of selectivity in increase of lysosomal enzymes in different situations and pathological states.

Language of Publication

English

Unique Identifier

99386061

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MeSH Heading (Major)

Acid Phosphatase|*AN; Cathepsin D|*AN; Lysosomes|*EN; Muscle Fibers|*EN; Seeds|*PO; Senna|*PO

MeSH Heading

Animal; Biological Markers|AN; Blotting, Western; Microscopy, Electron, Scanning Transmission; Rats; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

1122-9497

Country of Publication

ITALY

Record 92 from database: MEDLINE
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Title

Influence of Helicobacter pylori on tryptase and cathepsin D in peptic ulcer.

Author

Plebani M; Basso D; Rugge M; Vianello F; Di Mario F

Address

Istituto di Medicina di Laboratorio, University of Padova, Italy.

Source

Dig Dis Sci, 1995 Nov, 40:11, 2473-6

Abstract

We here ascertain whether tryptase (a serine endoprotease released by mast cells) and cathepsin D (CD, a lysosomal hydrolase that seems able to derange the extracellular matrix) play a part in peptic ulcer disease and whether they are linked to Helicobacter pylori (Hp) infection. We studied 13 controls, 25 patients with gastric ulcer, 47 with duodenal ulcer, and 11 with duodenitis. Tryptase and CD were measured in mucosal biopsies (body and antrum of the stomach and duodenum) using IRMA methods. Hp infection was histologically evaluated (Giemsa). Tryptase and CD levels were higher (25%) in patients with active peptic ulcer, whether gastric or duodenal. In Hp-positive patients the CD mucosal content was higher while tryptase mucosal levels were lower than in Hp-negative patients. Tryptase was correlated with gastrin content. CD seems to be mainly related to the phlogistic reaction of the mucosa to Hp infection; tryptase may reflect an indirect link between Hp infection, gastrin release, and the function of mast cells.

Language of Publication

English

Unique Identifier

96083476

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MeSH Heading (Major)

Cathepsin D|*ME; Helicobacter pylori|*/PH; Helicobacter Infections|*EN; Peptic Ulcer|*EN/*MI; Serine Proteinases|*ME

MeSH Heading

Adult; Duodenum|EN; Female; Gastric Mucosa|EN; Human; Inflammation Mediators|ME; Intestinal Mucosa|EN; Male; Mast Cells|EN; Middle Age; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0163-2116

Country of Publication

UNITED STATES

Record 93 from database: MEDLINE
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Title

Cathepsin B, L, and D activities in colorectal carcinomas: relationship with clinico-pathological parameters.

Author

Adenis A; Huet G; Zerimech F; Hecquet B; Balduyck M; Peyrat JP

Address

Laboratoire d'Oncologie MolÆeculaire Humaine, Centre Oscar Lambret. Lille, France.

Source

Cancer Lett, 1995 Sep, 96:2, 267-75

Abstract

Cathepsins, which are secreted by tumour and/or stromal cells, are thought to be involved in the degradative processes of tumour invasion and metastasis. The purpose of our study was to compare the cytosolic content of cathepsin B, L, and D in a series of matched malignant and adjacent normal colorectal tissues. Further we attempted to correlate these different proteinase values to classical clinico-pathological prognostic variables. Cathepsin B, L, and D activities were higher in tumour tissues than in normal mucosa (P < 10(-6), P < 0.004, P < 0.004, respectively) with median tumour/normal ratios of 7.9, 5.9, and 1.4, respectively. We found no difference in cathepsin B, L, and D activities either as a function of gender (except for cathepsin B values), age at time of surgery, tumour site, tumour differentiation, tumour stage (TNM or Astler-Coller staging system) or whether or not we found a mucinous component. Based on our data, cathepsin B seems to be the most discriminant parameter of the three proteinases that we studied, suggesting that cathepsin B expression may be of critical value in the progression of colorectal cancers.

Language of Publication

English

Unique Identifier

96030834

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MeSH Heading (Major)

Cathepsin B|AN/*ME; Cathepsin D|AN/*ME; Cathepsins|AN/*ME; Colorectal Neoplasms|*EN/*PA; Intestinal Mucosa|*EN

MeSH Heading

Aged; Aged, 80 and over; Colonic Neoplasms|EN/PA; Female; Human; Male; Middle Age; Prognosis; Rectal Neoplasms|EN/PA; Support, Non-U.S. Gov't; Tumor Markers, Biological|AN

Publication Type

JOURNAL ARTICLE

ISSN

0304-3835

Country of Publication

IRELAND

Record 94 from database: MEDLINE
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Title

Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression.

Author

Li YP; Chen W

Address

Department of Cytokine Biology, Forsyth Dental Center, Boston, Massachusetts, USA.

Source

J Bone Miner Res, 1999 Apr, 14:4, 487-99

Abstract

Cathepsin K, a lysosomal cysteine protease, is abundantly and selectively expressed in osteoclasts and has a specialized role in osteoclast-mediated bone resorption. In contrast to function studies, transcription regulation of cathepsin K remains largely unknown. In this study, the gene encoding mouse cathepsin K and the promoter have been isolated and completely sequenced. In addition, the temporal and spatial expressions of cathepsin K have been characterized. Intrachromosomal mapping studies revealed that the gene contains eight exons and seven introns spanning approximately 10.6 kb of genomic DNA, a genomic organization that was highly conserved with respect to its human homology. Analysis of the 9 kb 5' flanking region indicates that this gene lacks canonical TATA and CAAT boxes and contains multiple putative transcription regulatory elements which are also present in the comparable position of 5' flanking region of human cathepsin K gene. Mouse cathepsin K was found to be a single-copy gene. Northern blot analysis of RNAs from a number of mouse tissues revealed that cathepsin K mRNA is selectively expressed in osteoclast. The selective expression of cathepsin K was confirmed by anticathepsin K immunohistochemical staining. The sequence of cathepsin K expression was linked to osteoclast differentiation in vivo and in vitro by a tartrate-resistant acid phosphatase-anticathepsin K dual immunostaining technique. Cathepsin K is initially expressed at the preosteoclast stage and throughout the mature osteoclast stage. The primer extension assay indicated a major transcription start site 58 bp upstream of the initiator Met codon. The characterization of the cathepsin K gene, its promoter, and the temporal and spatial expression may provide valuable insights into its osteoclast-specific expression and the molecular mechanisms responsible for osteoclast activation.

Language of Publication

English

Unique Identifier

99250828

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MeSH Heading (Major)

Cathepsins|*GE

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Cell Differentiation; Cloning, Molecular; Comparative Study; DNA|GE; DNA Primers|GE; Exons; Gene Expression; Human; Introns; Mice; Molecular Sequence Data; Osteoclasts|CY/EN; Promoter Regions (Genetics); Restriction Mapping; RNA, Messenger|GE/ME; Sequence Homology, Nucleic Acid; Species Specificity; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0884-0431

Country of Publication

UNITED STATES

Record 95 from database: MEDLINE
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Title

Developmentally regulated secretion of cathepsin L-like cysteine proteases by Haemonchus contortus.

Author

Rhoads ML; Fetterer RH

Address

Livestock and Poultry Sciences Institute, United States Department of Agriculture, Beltsville, Maryland 20705, USA.

Source

J Parasitol, 1995 Aug, 81:4, 505-12

Abstract

Cysteine protease activity was present in media collected after 24 hr in vitro culture of adult Haemonchus contortus. The released cysteine protease hydrolyzed the fluorogenic 7-amino-4-trifluoromethyl coumarin (AFC)-substituted synthetic peptides Z-phe-arg-AFC and Z-ala-arg-arg-AFC, but not Z-arg-arg-AFC or Z-arg-AFC, characterizing this activity as cathepsin L-like. Within the parasite, cysteine protease activity was highest in extracts of intestinal tissue. Secreted cysteine protease inhibited the clotting of sheep blood and hydrolyzed hemoglobin, fibrinogen, collagen, and IgG; the IgG hydrolysis site was within the hinge region. Four proteases with M(r) values of 30, 34, 37, and 41 kDa were identified with biotinylated-phenylalanine-arginine-fluoromethyl ketone, a specific probe that binds to active cysteine proteases. Adult parasites cultivated in the presence of 0.1 mM levamisole released 50% less protease activity compared to control cultures; in the presence of rafoxanide (0.1 mM), protease was not detected. Cathepsin L-like cysteine protease activity was released also by L4, but not the L3 larval stage. The active and developmentally regulated release of cysteine proteases by H. contortus may have a critical function in worm nutrition, immune evasion, or both.

Language of Publication

English

Unique Identifier

95348878

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MeSH Heading (Major)

Cathepsins|*ME; Cysteine Proteinases|*ME; Haemonchus|DE/*EN

MeSH Heading

Amino Acid Sequence; Animal; Anthelmintics|PD; Blood Coagulation; Electrophoresis, Polyacrylamide Gel; Fluorescent Dyes|CH/ME; Hydrolysis; Larva|EN; Molecular Sequence Data; Proteins|ME; Sheep; Substrate Specificity

Publication Type

JOURNAL ARTICLE

ISSN

0022-3395

Country of Publication

UNITED STATES

Record 96 from database: MEDLINE
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Title

Preparation and characterization of monoclonal antibodies to human neutrophil cathepsin G, lactoferrin, eosinophil peroxidase, and eosinophil major basic protein.

Author

Skubitz KM; Christiansen NP; Mendiola JR

Address

Department of Medicine, University of Minnesota Medical School, Minneapolis.

Source

J Leukoc Biol, 1989 Aug, 46:2, 109-18

Abstract

This report describes the production and characterization of five murine monoclonal antibodies that react with granule proteins of human granulocytes. Monoclonal antibody AHN-11 (IgG2a) reacted specifically with neutrophil cathepsin G; no reactivity with the homologous neutrophil neutral proteases, elastase, proteinase 3, or esterase N was detected. Antibodies AHN-9 (IgG1) and AHN-9.1 (IgG2b) each reacted with different epitopes on human lactoferrin, but not with the homologous protein transferrin. Two IgG1 antibodies, AHE-1 and AHE-2, reacted specifically with eosinophils; AHE-1 reacted strongly with eosinophil peroxidase but not eosinophil major basic protein while AHE-2 recognized eosinophil major basic protein but not eosinophil peroxidase. All five antibodies could detect their respective antigens in alcohol-fixed cytospin preparations. These antibodies should be useful for immunolocalization and quantification of their respective antigens as well as for other studies of the roles of these proteins in granulocyte function and differentiation.

Language of Publication

English

Unique Identifier

89310278

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MeSH Heading (Major)

Antibodies, Monoclonal|AN/IM/*IP; Blood Proteins|*IM; Cathepsin D|*IM; Lactoferrin|*IM; Lactoglobulins|*IM; Neutrophils|*AN; Peroxidases|*IM

MeSH Heading

Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0741-5400

Country of Publication

UNITED STATES

Record 97 from database: MEDLINE
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Title

Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease.

Author

Papassotiropoulos A; Bagli M; Feder O; Jessen F; Maier W; Rao ML; Ludwig M; Schwab SG; Heun R

Address

Department of Psychiatry, University of Bonn, Germany. papassotiropoulos@uni-bonn.de

Source

Neurosci Lett, 1999 Mar, 262:3, 171-4

Abstract

The beta amyloid peptide derives from its precursor protein via proteolytic cleavage of yet unidentified proteases (beta- and gamma-secretases). Cathepsin D is an intracellular protease with in-vitro beta-secretase-like features. An exonic polymorphism of the cathepsin D gene (alanine to valine transition at position 224, exon 2) has been associated with altered enzyme function. We tested the hypothesis that this polymorphism is associated with an increased risk for Alzheimer's disease in 102 demented patients, 191 healthy subjects, and 160 depressed patients. There was a highly significant overrepresentation of the cathepsin D*T allele in demented patients (14.2%) compared to non-demented controls (6.7%, P = 0.0012). Carriers of the cathepsin D*T allele had a 2.4-fold increased risk for developing AD than non-carriers. Carriers of the apolipoprotein E epsilon 4 allele had a 4.1 -fold increased risk than non-carriers. The odds ratio for subjects with the apolipoprotein E epsilon 4 and the cathepsin D*T allele was 5.9. Our data suggest that the cathepsin D genotype is strongly associated with the risk for Alzheimer's disease.

Language of Publication

English

Unique Identifier

99233251

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MeSH Heading (Major)

Alzheimer Disease|EN/*GE; Cathepsin D|*GE; Genetic Predisposition to Disease|*; Polymorphism (Genetics)|*

MeSH Heading

Aged; Aged, 80 and over; Alanine; Amino Acid Substitution; Apolipoproteins E|GE; Comparative Study; Depression|GE; Exons; Female; Genotype; Heterozygote Detection; Human; Male; Middle Age; Reference Values; Risk Factors; Support, Non-U.S. Gov't; Valine

Publication Type

JOURNAL ARTICLE

ISSN

0304-3940

Country of Publication

IRELAND

Record 98 from database: MEDLINE
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Title

Cathepsin D-like activity in neutrophils and monocytes.

Author

Levy J; Kolski GB; Douglas SD

Address

Division of Allergy-Immunology-Bone-Marrow Transplantation, Children's Hospital of Philadelphia, Pennsylvania.

Source

Infect Immun, 1989 May, 57:5, 1632-4

Abstract

Monocytes-macrophages and polymorphonuclear leukocytes contain an acid proteolytic enzyme that cleaves tritiated hemoglobin. The monocyte-macrophage-derived enzymatic activity was completely inhibited by pepstatin A, a property of cathepsin D. Monocyte-derived macrophages developed detectable cathepsin D-like activity after 5 days in culture, and this activity coincided with the appearance of other known indicators of macrophage maturation. The cathepsin D activity further increased significantly with time after day 5 of culture. The proteinase activity extracted from neutrophils was only partially inhibitable by pepstatin A, which indicates that this activity is contributed by more than one proteolytic enzyme, including cathepsin D. Cathepsin D activity demonstrated in neutrophils and macrophages may be an important marker of phagocyte function.

Language of Publication

English

Unique Identifier

89212920

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MeSH Heading (Major)

Cathepsin D|*BL; Monocytes|*EN; Neutrophils|*EN

MeSH Heading

Hemoglobins|ME; Human; Hydrogen-Ion Concentration; In Vitro; Macrophages|EN; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0019-9567

Country of Publication

UNITED STATES

Record 99 from database: MEDLINE
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Title

Cloning and expression of a rat placental cDNA encoding a novel cathepsin L-related protein.

Author

Conliffe PR; Ogilvie S; Simmen RC; Michel FJ; Saunders P; Shiverick KT

Address

Department of Pharmacology and Therapeutics, University of Florida, Gainesville 32610, USA.

Source

Mol Reprod Dev, 1995 Feb, 40:2, 146-56

Abstract

Cathepsin L is a major lysosomal cysteine protease produced by mouse placenta and fibroblasts. This study characterizes a novel cathepsin L-related mRNA expressed in rat placenta. Immunological and nucleotide screening of a rat placenta library identified six positive clones, the largest, pCLRP-9, being 924 base pairs in length. The combined sequences of all the clones contain an open reading frame of 711 nucleotides, a termination codon, a polyadenylation site, and 197 nucleotides of 3' untranslated region, but lack the 5' translation initiation codon. The pCLRP nucleotide sequence showed 60-64% identity to those of mouse, rat, and human cathepsin L. The deduced amino acid sequence of pCLRP codes for 237 amino acids, which align with the carboxy-terminal sequence of cathepsin L and has the active site residues characteristic of the cysteine protease family. Northern blot analysis showed hybridization of pCLRP with a major mRNA transcript of 1.3 kilobases expressed in placenta, but not kidney or liver. In contrast, a cDNA for mouse pro-cathepsin L hybridized with a transcript of 1.7 kilobases expressed in rat kidney, as well as placenta. During late gestation, steady-state levels of rat placental pCLRP mRNA were highest on day 18, whereas those of mouse procathepsin L were greatest on day 20 of gestation. Antiserum to mouse cathepsin L cross-reacted with four proteins of molecular weights 36,000 to 42,000 in rat placental culture medium, of which two were absent in the kidney. These data indicate that rat placenta expresses several species of cathepsin L-type proteins, which may be involved in placental function and nutrient supply.

Language of Publication

English

Unique Identifier

95283809

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MeSH Heading (Major)

Cathepsins|*BI/CH; Cysteine Proteinases|*BI/CH; Gene Expression|*; Placenta|*ME

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Cats; Cloning, Molecular; Comparative Study; DNA, Complementary; Female; Gene Library; Human; Immunoblotting; Mice; Molecular Sequence Data; Polymerase Chain Reaction; Pregnancy; Rats; Restriction Mapping; RNA, Messenger|AN/BI; Sequence Homology, Amino Acid; Support, U.S. Gov't, P.H.S.; Transcription, Genetic

Publication Type

JOURNAL ARTICLE

ISSN

1040-452X

Country of Publication

UNITED STATES

Record 100 from database: MEDLINE
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Title

Germ cell-Sertoli cell interactions: regulation by germ cells of the stage-specific expression of CP-2/cathepsin L mRNA by Sertoli cells.

Author

Wright WW; Zabludoff SD; Penttilä TL; Parvinen M

Address

Department of Population Dynamics, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.

Source

Dev Genet, 1995, 16:2, 104-13

Abstract

CP-2/cathepsin L mRNA is expressed primarily by rat Sertoli cells within stage VI-VIII seminiferous tubules. To test whether germ cells regulated this expression, we examined if separating Sertoli cells from specific germ cells affected expression of this transcript in Sertoli cells. First, Sertoli cells were isolated from adult (90-day-old) and immature (25-day-old) rats and levels of this transcript measured immediately or after 1, 3 and 5 days in culture. Results demonstrated that immediately upon isolation, CP-2/cathepsin L mRNA levels were significantly higher in mature cells. However, after 1 day in culture, the levels of this transcript increased in immature cells and remained high in mature cells. We therefore conclude that in vivo, a subset of germ cells inhibit the expression of CP-2/cathepsin L mRNA by immature Sertoli cells. Second, to examine the effect of specific germ cells on CP-2/cathepsin L mRNA expression, we exposed the testes of mature rats to 3 Gy of gamma-radiation and analyzed stage-specific expression of this transcript at varying times during maturation depletion and subsequent germ cell restoration. Loss of spermatogonia or spermatocytes was without effect. However, when pachytene spermatocytes through step 14 spermatids were depleted, expression at stages VI-VIII was reduced by half and expression at stages IX-I was increased 14-fold. These changes resulted in the loss of stage-specific expression of CP-2/cathepsin L mRNA by Sertoli cells. Finally, stage VI-VIII tubules, depleted primarily in step 15-19 spermatids, had levels of CP-2/cathepsin L mRNA that were 60% of control. However, stage-specific expression of this transcript was detected in these tubules. In contrast to what we noted with CP-2/cathepsin L mRNA, loss and restoration of germ cells had no effect on Sertoli cell levels of SGP-2 mRNA, indicating that testicular irradiation had no overall effect on Sertoli cell function. Taken together, these data suggest that the stage-specific expression of the CP-2/cathepsin L gene results from the sequential stimulation and inhibition of Sertoli cells by germ cells, that pachytene spermatocytes through step 14 spermatids are required for this stage-specific expression and that step 18 and 19 spermatids amplify this expression at stages VI-VIII.

Language of Publication

English

Unique Identifier

95254738

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MeSH Heading (Major)

Cathepsins|*GE; Gene Expression Regulation|*; Sertoli Cells|*CY/EN/PH; Spermatozoa|*CY/EN/PH

MeSH Heading

Animal; Cell Communication; In Vitro; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger|GE/ME; Spermatogenesis; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Testis|CY/RE

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Publication Type

JOURNAL ARTICLE

ISSN

0192-253X

Country of Publication

UNITED STATES