Atlas of Genetics and Cytogenetics in Oncology and Haematology
CTSH (cathepsin H)
| Identity |
| Other names | ACC-4 |
| ACC-5 | |
| CPSB | |
| DKFZp686B24257 | |
| EC 3.4.22.16 | |
| MGC1519 | |
| aleurain | |
| minichain | |
| HGNC (Hugo) | CTSH |
| Location | 15q25.1 |
| Location_base_pair | Starts at 77001147 and ends at 77024475 bp from pter ( according to hg18-Mar_2006) [Mapping] |
| DNA/RNA |
| Description | The gene for human cathepsin H is located on chromosome 15q24-q25 and contains 12 exons spanning over 23 kb of genomic sequences. The junctions between the exons and 11 introns conform to the GT-AG rule. The preproenzyme transcript length is 1005 bp. |
| Transcription | The cathepsin H gene has a TATA- and CAAT-less promoter and upstretream of exon 1 only one GC box was detected, suggesting the presence of one more exon. Two different forms of cathepsin H cDNA, the full-length form (CTSH) and a truncated form with deletion of 12 amino acids at the signal peptide region (CTSHdelta10-21), were identified in prostate tissues and cancer cell lines. |
| Protein |
 | |
| Richardson diagram of cathepsin H structure: a-helixes are shown in red and ß -sheets in green. Catalytic residues are shown in ball-and-stick representation: Cys141 in yellow, His281 in purple and Asn301 in pink. Carbohydrates are shown as CPK spheres in yellow. The mini chain is shown in grey (MEROPS: the peptidase database - C01.040). | |
| Description | Cathepsin H belongs to the superfamily of papain-like cysteine proteases. It is synthesized as a preproenzyme of 335 amino acid residues with a calculated Mr of 37 403. It is proteolytically processed to an active single chain, i.e. mature form within the endosomes/lysosomes. A unique feature of this enzyme is that it acts as both an aminopeptidase and an endopeptidase although the latter activity is much lower than the former activity. Sequencing data revealed that in addition to the heavy and light chains, which are typically found in a number of mammalian papain-like cysteine proteases, cathepsin H contains also an octapeptide EPQNCSAT originating from the propeptide, termed the mini-chain. It was shown that the mini-chain is disulfide linked to Cys205 of the main body of the enzyme and involved in the aminopeptidase activity of the enzyme. It was concluded that the mini-chain plays a key role in substrate recognition, and that the carbohydrate residues attached to the body of the enzyme are involved in the positioning the mini-chain in the active-site cleft. Procathepsin H has three potential carbohydrate binding sites. Glycosilation has been confirmed on Asn230 and on the mini-chain Asn101 of the mature enzyme. The recombinant form of human cathepsin H lacking the mini-chain was shown to be an endopeptidase. Cathepsin H hidrolyzes endopeptidase substrates such as Bz-Arg+NHNap, Bz-Arg+NHMec, Bz-Phe-Val-Arg+NHMec, and acts on Pro-Gly+Phe and Pro-Arg+NHNap much like a dipeptidyl-peptidase. It was shown to cleave several proteins preferring hydrophobic residues at P2 and P3, however the endopeptidase activity of the enzyme is limited. Collagen and laminin, for instance, were not degraded by cathepsin H. Naturally occurring inhibitors of cathepsin H are the cystatins, a2-macroglobulin and antigens from mouse cytotoxic lymphocytes CTLA-2ß. |
| Expression | Cathepsin H expression is ubiquitous, with very high expression in the kidney. There is growing evidence that the expression of cathepsin H is increased in diseases including breast, colorectal and prostate carcinoma, melanoma and gliomas. In contrast, decreased cathepsin H expression has been reported in squamous cell carcinoma of the head and neck. Other studies have found a higher cathepsin H expression in well-differentiated pancreatic cancer cells compared with less well-differentiated cancer cells. |
| Localisation | Cathepsin H is located manly at the endosomal-lysosomal compartments. Only 10 % of the enzyme is secreted. It has been shown that substantial concentrations of cathepsin H circulate in the blood. |
| Function | Cathepsin H is one of the lysosomal cysteine proteinases, which are involved in intracellular protein degradation. It is one of the few noncomplement proteases that cleave native C5 to generate the potent chemotaxin C5a. Cathepsin H was detected in extracellular compartments of atherosclerotic plaques. Although the pathogenic potential of cathepsin H in the development of the late, unstable plaque is quite evident, there is the possibility that this protease may play a role in early atherogenesis. Furthermore, it was found that cathepsin H could contribute to the transformation of LDL in monocyte-derived foam cells. Recently the enzyme was shown to be essential in one of the processing steps of hydrophobic surfactant-associated protein C. Cathepsin H is overexpressed in different tumour cells. However, the role of cathepsin H in tumour progression is not well understood. A possible function of cathepsin H in tumour progression is its ability to degrade fibrinogen and fibronectin, suggesting that, along with other proteases, cathepsin H may be involved in the destruction of extracellular matrix components leading to cancer proliferation, migration, and metastasis. |
| Homology | Cathepsins H exhibit a high degree of sequence homology to cathepsin B and other cysteine proteinases of the C1 (papain) family. |
| Mutations |
| Germinal | Not yet reported |
| Somatic | Not yet reported |
| Implicated in |
| Entity | Colorectal cancer |
| Prognosis | Protein levels of cathepsin H were measured by ELISA in preoperative sera from 324 patients with colorectal cancer. The level of cathepsin H was significantly increased in patient sera, the median level was 8.4 ng/mL versus 2.1 ng/mL in 90 healthy blood donors (p < 0.0001). In survival analysis a significant difference was found between the group of patients with low cathepsin H (first tertile) who had a poor prognosis and the remaining patients (p = 0.03). The risk of patients was further stratified when cathepsin H levels were combined with carcinoembryonic antigen (CEA). Patients with high CEA and low cathepsin H had the highest risk of death with a hazard ratio of 2.72 (95% CI 1.73-4.28), p < 0.0001.The prognostic information of cathepsin H differs from that of the related cathepsins B and L and suggest different roles during the progression of malignant disease. |
| Entity | Melanoma |
| Prognosis | The level of cathepsin H was determined in the sera of 43 patients with metastatic melanoma, in 54 patients with treated cutaneous melanoma with no evidence of metastatic disease, and in 30 healthy blood donors, using quantitative ELISA. The levels were significantly higher within the group of metastatic melanoma patients compared with the healthy controls with a median of 13.7 versus 4.9 ng/ml (P < 0.0001). Cathepsin H was also significantly increased within the group of melanoma patients with no metastasis, with a median of 9.6 ng/ml. The serum level was increased in patients showing no response to the chemoimmunotherapy as compared to the level in responders. Metastatic melanoma patients with high content of cathepsin H experienced significantly shorter overall survival rates than the patients with low levels of the enzyme (Cat H: P < 0.006 and relative risk, 2.4, using median as cut-off value). |
| Entity | Head and neck carcinoma |
| Prognosis | To estimate the prognostic value of cathepsins H in head and neck carcinoma, its concentration was measured in cytosols of primary tumours and adjacent normal tissue from 21 patients. Cathepsin H concentration was higher in normal tissue (p = 0.001) than in tumour tissue and in laryngeal than in non-laryngeal normal and tumour tissues. Disease-free survival was poor in patients with lower concentrations of cathepsin H in tumour tissue (p = 0.055). |
| Entity | Bladder cell transitional cell carcinoma |
| Note | Using spectrofluorometric assay, catalytic activity of cathepsin H was measured in human bladder cell lines (HCV29, normal; RT4, well differentiated; J82, poorly differentiated) and in noncancerous and cancerous tissue samples (n = 20) of transitional cell carcinoma. In comparison to the intracellular activity of cathepsin H in the poorly differentiated cell line J82, the intracellular activity in the normal cell line HCV29 was significantly greater (P <0.05), independent of stage or grade. In contrast, the portion of cathepsin H released from cell line J82 into the supernatant, revealed higher values than that from cell line HCV29. In cancerous bladder tissue, the level of cathepsin H was significantly greater than in the matched normal tissue (P <0.05). |
| Entity | Lung cancer |
| Note | A transgenic mouse model of lung cancer was utilized to identify markers of early lung tumours in humans. Immunohistochemical analyses identified cathepsin H as being consistently elevated in the murine lung tumours compared to non-tumour bearing transgenic lung tissue surrounding the tumour. Importantly, the elevation was observed in early stage, indicating its ability to detect early lung lesions that would be amenable to surgical resection. |
| Entity | Glioma |
| Note | Cathepsin H activity was determined in normal brain tissue and tumour tissue extracts. The activity of cathepsin H was twofold higher in low grade glioma, fourfold higher in anaplastic astrocytoma and eightfold higher in glioblastoma than in normal brain tissue. Cathepsin H antibody inhibited the invasion of glioblastoma cell lines through Matrigel®. These data suggest that the tumour-specific increase in antigen may be a useful independent marker of tumour progression in central nervous system neoplasms. |
| Entity | Cervical carcinoma |
| Note | The expression of cathepsin H in cervical carcinoma cell lines and tissue was found to be down-regulated compared to normal tissue, using cDNA arrays. |
| Entity | Joint diseases |
| Note | The level of cathepsin H was determined in synovial fluids and sera of patients with inflammatory and metabolic joint diseases, using quantitative ELISA. Cathepsin H was not found in normal sera (values below 3 micrograms/l), but was measurable in patients' synovial fluids. The highest values of cathepsin H were measured in synovial fluids of patients with undifferentiated arthritis. There is yet no clear correlation between the quantity of the enzyme released in synovia and the clinical diagnosis or the stage of disease. |
| Entity | Alzheimer's disease |
| Note | Cultured fibroblasts from patients affected by Alzheimer's disease (AD) exhibited alterations of the enzyme transketolase. Abnormalities (dubbed alkaline band) consisted of enzyme forms having unusually high pl and were proposed as a marker of the disease in living patients. Human cathepsin H was shown to partially induce an Alzheimer-like transketolase pattern and cleave normal transketolase to a 35 kDa fragment as spontaneously occurring in Alzheimer's disease fibroblasts. The explanation of transketolase abnormalities could be an imbalance of proteolysis in Alzheimer's disease fibroblasts due to a relative increase/derangement of cysteine proteinases, including cathepsin H. |
| External links |
| Bibliography |
| Generation of biologically active, complement-(C5) derived peptides by cathepsin H. |
| Perez HD, Ohtani O, Banda D, Ong R, Fukuyama K, Goldstein IM |
| Journal of immunology (Baltimore, Md. : 1950). 1983 ; 131 (1) : 397-402. |
| PMID 6408181 |
| Distribution of cathepsins B and H in rat tissues and peripheral blood cells. |
| Kominami E, Tsukahara T, Bando Y, Katunuma N |
| Journal of biochemistry. 1985 ; 98 (1) : 87-93. |
| PMID 3900059 |
| The cystatins: a diverse superfamily of cysteine peptidase inhibitors. |
| Barrett AJ |
| Biomedica biochimica acta. 1986 ; 45 (11-12) : 1363-1374. |
| PMID 3555466 |
| Intracellular transport and processing of lysosomal cathepsin H. |
| Nishimura Y, Kato K |
| Biochemical and biophysical research communications. 1987 ; 148 (1) : 329-334. |
| PMID 3675581 |
| Report of the committee on the genetic constitution of chromosomes 13, 14, 15 amd 16. |
| Ropers HH, Gedde-Dahl T Jr, Cox DW |
| Cytogenetics and cell genetics. 1987 ; 46 (1-4) : 213-241. |
| PMID 3507275 |
| Molecular cloning and sequencing of a cDNA coding for mature human kidney cathepsin H. |
| Fuchs R, Machleidt W, Gassen HG |
| Biological chemistry Hoppe-Seyler. 1988 ; 369 (6) : 469-475. |
| PMID 2849458 |
| Amino acid sequences of the human kidney cathepsins H and L. |
| Ritonja A, PopoviŸá T, Kotnik M, Machleidt W, Turk V |
| FEBS letters. 1988 ; 228 (2) : 341-345. |
| PMID 3342889 |
| Gene structure of rat cathepsin H. |
| Ishidoh K, Kominami E, Katunuma N, Suzuki K |
| FEBS letters. 1989 ; 253 (1-2) : 103-107. |
| PMID 2759235 |
| Interaction of lysosomal cysteine proteinases with alpha 2-macroglobulin: conclusive evidence for the endopeptidase activities of cathepsins B and H. |
| Mason RW |
| Archives of biochemistry and biophysics. 1989 ; 273 (2) : 367-374. |
| PMID 2476070 |
| Determination of cathepsins B and H in sera and synovial fluids of patients with different joint diseases. |
| Gabrijelcic D, Annan-Prah A, Rodic B, Rozman B, Cotic V, Turk V |
| Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie. 1990 ; 28 (3) : 149-153. |
| PMID 2329322 |
| S-S bridges of cathepsin B and H from bovine spleen: a basis for cathepsin B model building and possible functional implications for discrimination between exo- and endopeptidase activities among cathepsins B, H and L. |
| Baudys M, Meloun B, Gan-Erdene T, Fusek M, Mares M, Kostka V, Pohl J, Blake CC |
| Biomedica biochimica acta. 1991 ; 50 (4-6) : 569-577. |
| PMID 1801725 |
| Characterization of a cathepsin-H-like enzyme from a human melanoma cell line. |
| Tsushima H, Ueki A, Matsuoka Y, Mihara H, Hopsu-Havu VK |
| International journal of cancer. Journal international du cancer. 1991 ; 48 (5) : 726-732. |
| PMID 2071233 |
| Studies on the aminopeptidase activity of rat cathepsin H. |
| Rothe M, Dodt J |
| European journal of biochemistry / FEBS. 1992 ; 210 (3) : 759-764. |
| PMID 1483460 |
| The specificity and elastinolytic activities of bovine cathepsins S and H. |
| Xin XQ, Gunesekera B, Mason RW |
| Archives of biochemistry and biophysics. 1992 ; 299 (2) : 334-339. |
| PMID 1444473 |
| Inhibition of cathepsin L-like cysteine proteases by cytotoxic T-lymphocyte antigen-2 beta. |
| Delaria K, Fiorentino L, Wallace L, Tamburini P, Brownell E, Muller D |
| The Journal of biological chemistry. 1994 ; 269 (40) : 25172-25177. |
| PMID 7929206 |
| Cathepsin S and related lysosomal endopeptidases. |
| Kirschke H, Wiederanders B |
| Methods in enzymology. 1994 ; 244 : 500-511. |
| PMID 7845228 |
| Proteinases 1: lysosomal cysteine proteinases. |
| Kirschke H, Barrett AJ, Rawlings ND |
| Protein profile. 1995 ; 2 (14) : 1581-1643. |
| PMID 8771190 |
| Prognostic value of cathepsins B, H, L, D and their endogenous inhibitors stefins A and B in head and neck carcinoma. |
| Budihna M, Strojan P, Smid L, Skrk J, Vrhovec I, Zupevc A, Rudolf Z, Zargi M, Krasovec M, Svetic B, Kopitar-Jerala N, Kos J |
| Biological chemistry Hoppe-Seyler. 1996 ; 377 (6) : 385-390. |
| PMID 8839984 |
| Expression and the role of cathepsin H in human glioma progression and invasion. |
| Sivaparvathi M, Sawaya R, Gokaslan ZL, Chintala SK, Rao JS |
| Cancer letters. 1996 ; 104 (1) : 121-126. |
| PMID 8640738 |
| Cathepsins B, H, and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. |
| Kos J, Stabuc B, Schweiger A, Krasovec M, Cimerman N, Kopitar-Jerala N, Vrhovec I |
| Clinical cancer research : an official journal of the American Association for Cancer Research. 1997 ; 3 (10) : 1815-1822. |
| PMID 9815568 |
| Cysteine proteinases are responsible for characteristic transketolase alterations in Alzheimer fibroblasts. |
| Paoletti F, Mocali A, Tombaccini D |
| Journal of cellular physiology. 1997 ; 172 (1) : 63-68. |
| PMID 9207926 |
| Enzyme-linked immunosorbent assay for the detection of total cathepsin H in human tissue cytosols and sera. |
| Schweiger A, Stabuc B, Popovˆ‚c T, Turk V, Kos J |
| Journal of immunological methods. 1997 ; 201 (2) : 165-172. |
| PMID 9050938 |
| 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. |
| Guncar G, Podobnik M, Pungercar J, Strukelj B, Turk V, Turk D |
| Structure (London, England : 1993). 1998 ; 6 (1) : 51-61. |
| PMID 9493267 |
| Cathepsins B, H, L and cysteine protease inhibitors in malignant prostate cell lines, primary cultured prostatic cells and prostatic tissue. |
| Friedrich B, Jung K, Lein M, Tˆºrk I, Rudolph B, Hampel G, Schnorr D, Loening SA |
| European journal of cancer (Oxford, England : 1990). 1999 ; 35 (1) : 138-144. |
| PMID 10211102 |
| Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas. |
| del Re EC, Shuja S, Cai J, Murnane MJ |
| British journal of cancer. 2000 ; 82 (7) : 1317-1326. |
| PMID 10755408 |
| Lysosomal cysteine protease, cathepsin H, is targeted to lysosomes by the mannose 6-phosphate-independent system in rat hepatocytes. |
| Tanaka Y, Tanaka R, Himeno M |
| Biological & pharmaceutical bulletin. 2000 ; 23 (7) : 805-809. |
| PMID 10919356 |
| Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array. |
| Tung WS, Lee JK, Thompson RW |
| Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2001 ; 34 (1) : 143-150. |
| PMID 11436088 |
| Involvement of cathepsin H in the processing of the hydrophobic surfactant-associated protein C in type II pneumocytes. |
| Brasch F, Ten Brinke A, Johnen G, Ochs M, Kapp N, Mˆºller KM, Beers MF, Fehrenbach H, Richter J, Batenburg JJ, Bˆºhling F |
| American journal of respiratory cell and molecular biology. 2002 ; 26 (6) : 659-670. |
| PMID 12034564 |
| Analysis of a truncated form of cathepsin H in human prostate tumor cells. |
| Waghray A, Keppler D, Sloane BF, Schuger L, Chen YQ |
| The Journal of biological chemistry. 2002 ; 277 (13) : 11533-11538. |
| PMID 11796715 |
| Enzymatically modified LDL induces cathepsin H in human monocytes: potential relevance in early atherogenesis. |
| Han SR, Momeni A, Strach K, Suriyaphol P, Fenske D, Paprotka K, Hashimoto SI, Torzewski M, Bhakdi S, Husmann M |
| Arteriosclerosis, thrombosis, and vascular biology. 2003 ; 23 (4) : 661-667. |
| PMID 12615673 |
| Recombinant human cathepsin H lacking the mini chain is an endopeptidase. |
| Vasiljeva O, Dolinar M, Turk V, Turk B |
| Biochemistry. 2003 ; 42 (46) : 13522-13528. |
| PMID 14621998 |
| Serum cathepsin H as a potential prognostic marker in patients with colorectal cancer. |
| Schweiger A, Christensen IJ, Nielsen HJ, Sˆ½rensen S, Brˆºnner N, Kos J |
| The International journal of biological markers. 2004 ; 19 (4) : 289-294. |
| PMID 15646835 |
| Use of a transgenic mouse model to identify markers of human lung tumors. |
| Linnerth NM, Sirbovan K, Moorehead RA |
| International journal of cancer. Journal international du cancer. 2005 ; 114 (6) : 977-982. |
| PMID 15645424 |
| Overexpression of cathepsin F, matrix metalloproteinases 11 and 12 in cervical cancer. |
| Vazquez-Ortiz G, Pina-Sanchez P, Vazquez K, Duenas A, Taja L, Mendoza P, Garcia JA, Salcedo M |
| BMC cancer. 2005 ; 5 (1) : page 68. |
| PMID 15989693 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 09-2007 | Zala Jevnikar, Janko Kos |
| Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia |
| Citation |
| This paper should be referenced as such : |
| Jevnikar Z, Kos J . CTSH (cathepsin H). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CTSHID40206ch15q25.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Feb 27 10:53:11 CET 2010 |
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