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Kallikrein-Related Peptidase 7) View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Queensland University of Technology ePrints Archive This is the author’s version of a work that was submitted/accepted for pub- lication in the following source: Dong, Ying, Lai, John,& Clements, Judith (2010) KLK7 (kallikrein-related peptidase 7). Atlas of Genetics and Cytogenetics in Oncology and Haema- tology, 14(4), pp. 388-396. This file was downloaded from: http://eprints.qut.edu.au/57842/ c Copyright 2010 The Authors & ATLAS This work is licensed under a Creative Commons Attribution- Noncommercial-No Derivative Works 2.0 France Licence. Notice: Changes introduced as a result of publishing processes such as copy-editing and formatting may not be reflected in this document. For a definitive version of this work, please refer to the published source: Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review KLK7 (kallikrein-related peptidase 7) Ying Dong, John Lai, Judith A Clements Hormone Dependent Cancer Program, Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia (YD, JL, JAC) Published in Atlas Database: May 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/KLK7ID41087ch19q13.html DOI: 10.4267/2042/44734 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology and ovarian cells, suggesting the expression of tissue Identity specific KLK7 transcripts. Other names: PRSS6; SCCE; hK7; hSCCE Pseudogene HGNC (Hugo): KLK7 Not identified. Location: 19q13.33 Local order: Telomere to centromere. Protein DNA/RNA Description Full-length KLK7 (253 amino acids) has a secretion Description signal (pre-) peptide (22 amino acids), followed by an The gene encompasses 6.509 kb of gDNA. activation (pro-) peptide (7 amino acids) and the mature chain (224 amino acids) with 1 potential N-linked Transcription glycosylation site. The catalytic triad of His70, Asp112 Five variant mRNA transcripts have been identi-fied. and Ser205 (relative to ATG1) is conserved and is These include transcripts using different 5' untranslated essential for proteolytic activity. After synthesis as a regions (UTRs) including exon 1 deletions, and KLK7 full-length protein, the signal peptide is then transcripts using different 3'UTR regions. Using rapid cleaved and pro-KLK7 (zymogen) is subsequently amplification of cDNA ends (RACE) different KLK7 secreted from the cell. On activation, the propeptide is 5'UTR sequences were identified from RNA extracted removed and the zymogen becomes the mature active from pancreas, skin enzyme. Genomic and protein structure of the KLK7 gene. The KLK7 gene is classically comprised of 5 coding exons (red boxes, classic numerals) and 4 intervening introns with a conserved intron phase pattern (I, II, I, 0). A non-coding exon and untranslated regions are shown in yellow. Also shown is the classical transcription initiation site (TIS) and corresponding translation start site (ATG1). An exon 1 deleted transcript has also been identified which would potentially result in the use of an alternative translation start site (ATG2). The numbering for the amino acid residues of the catalytic triad (His70, Asp112, Ser205) are relative to the full-length protein starting from ATG1. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4) 389 KLK7 (kallikrein-related peptidase 7) Dong Y, et al. KLK7 can complex with antileukoprotease (secretory human body fluid, such as, seminal plasma, breast leukocyte protease inhibitor), elafin, Lympho-epithelial milk, ovarian cancer ascites, salivary and Kazal type inhibitor (LEKTI) fragments, and a member cervicovaginal fluid. of a2-macroglobulin (a2M) protease inhibitor family, In normal skin, KLK7 is expressed in late epidermal a2-macroglobulin-like 1 (a2ML1). differentiation and found at all sites of epithelial X-ray structures of recombinant full-length KLK7 from cornification. Consequently, KLK7 is used as a marker E. coli and insect cells have been solved, from which for terminal epidermal differentia-tion. In normal the most distinguishing features of KLK7 are the short epidermis, KLK7 was detected in a population of 70-80 loop and the unique S1 pocket, which prefers P1 dendritic cells and in high suprabasal keratinocytes. Tyr residues. KLK7 displays a unique chymotrypsin- KLK7 was also found in reconstruct-ted human like specificity for Tyr, which is preferred at P2. In epidermis and its expression was suppressed by retinoic addition, KLK7 exhibits large positively charged acid. An increased expres-sion of KLK7 was found in surface patches, representing putative exosites for suprabasal cells in orthokeratotic and parakeratotic prime side substrate recognition. areas of the lesions of oral lichen planus (an Similar to several other KLKs and based on the binding inflammatory disease) and benign oral keratosis (a non- inflammatory disease). of metal to histidine such as His99, the KLK7 activity is inhibited by Zn++ and Cu++ at low micromolar High KLK7 protein levels have been detected in the concentrations. KLK7 induced degradation of tissues of lung, breast, ovarian and squamous cervical corneodesmosin and desmocollin 1 with similar cancers, oral squamous cell carcinoma and cervical efficiency in acidic (pH 5.6) and neutral (pH 7.2) adenocarcinoma tissues from patients. However, KLK7 conditions. KLK7 activity is modulated by water is down regulated in cancerous prostate tissues content in stratum corneum as KLK7 activity increased compared to normal prostate tissues. KLK7, along with significantly in an environment of high relative KLK6 and KLK10, is decreased in cerebrospinal fluid humidity. KLK7 also demonstrated a tolerance to water of frontotemporal dementia patients. restriction suggesting that it may be adapted to function Localisation in the water-restricted stratum corneum. Thus, relative humidity modulates desquamation by its effect upon Full-length KLK7 is localised intracellularly in the KLK7 activity, possibly other desquamatory hydrolases cytoplasm prior to secretion. KLK7 protein is co- and adapted KLK7 function in water-deplete skin. localised with KLK5 in skin and acinar cells of the pancreas by immunohistochemical staining. An N-terminal truncated KLK7 isoform (181 amino acids) initiating from the putative ATG2 would not The putative N-terminal truncated KLK7-181 isoform have the pre-pro-region and 43 amino acids from the is potentially not secreted as it does not have a signal N-terminus of full-length KLK7. The histidine which is peptide, and cellular localisation remains to be part of the catalytic triad is also omitted which would determined. result in a proteolytic inactive protein. The presence of Function this isoform has not yet been confirmed in human tissues or biological fluids. To date, the major biological functions of KLK7 are associated with the skin and related epithelial tissues, Expression such as hair follicles, oral mucosa and glandular Full-length KLK7 protein was originally purified in lobules. KLK7 is involved in keratiniza-tion, stratum human skin and named stratum corneum chymotryptic corneum formation, and turnover/ desquamation of the enzyme (SCCE, hSCCE). KLK7 cDNA was originally skin through the degradation of cell adhesion isolated from a keratinocyte derived library and glycoproteins, such as corneodes-mosin, desmocollin 1 designated PRSS6. Although Northern blot analyses and plakoglobin. KLK7 has also been shown to cleave have shown that KLK7 mRNA is predominantly insulin B chain, degrade fibronectin, fibrinogen and localised to skin and pancreas, more sensitive RT-PCR interleukin 1beta (IL-1b), as well as activate pro-IL-1b. experiments have shown that brain, kidney, ovary, KLK7 and KLK5 can control activation of the human bone, breast, endometrium, spinal cord, lung, prostate cathelicidin precursor protein, hCAP18, implying their tissue and salivary tissue express KLK7 mRNA at low ability to control innate immune defence. to modest levels. High KLK7 mRNA has been detected An in vitro study showed that UVB radiation can in malignancies of ovary, breast, lung and brain. increase KLK7 and KLK5 expression at both mRNA KLK7 protein has been detected by ELISA in a wide and protein levels in keratinocyte (HaCat) cells. In the range of tissues at low (adrenal, bladder, cervix, epidermis, the major inhibitor of KLK7, fallopian tube, kidney, lung, lymph node, muscle, antileukoprotease (secretory leukocyte protease ovary, salivary gland, small intestine, spinal cord, inhibitor) is produced by keratinocytes and can inhibit spleen, thyroid gland, tonsil, trachea and vagina) to detachment of corneocytes from human plantar callus high (oesophagus, heart, liver and skin) levels. Modest in vitro, while a weaker KLK7 inhibitor, elafin (skin- levels of KLK7 protein have also been detected in derived antileukoprotease), can reduce the shedding of Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4) 390 KLK7 (kallikrein-related peptidase 7) Dong Y, et al. corneocytes. Established epidermal mouse models 1 deleted short KLK7 transcripts were detected in overexpressing KLK7 have been shown to develop serous EOC cells, while none or only KLK7 short chronic itchy dermatitis. Further characterisation of transcript was found in normal ovarian epithelial cells. these models also revealed epidermal In addition, a coordinated expression
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