CTSL1 (cathepsin L1)

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CTSL1 (cathepsin L1)

Identity

Other names	CATL
	CTSL
	EC 3.4.22.15
	FLJ31037
	MEP
	OTTHUMP00000021601
	OTTHUMP00000021602
	OTTHUMP00000063566
HGNC (Hugo)	CTSL1
Location	9q21.33
Location_base_pair	Starts at 89530794 and ends at 89536202 bp from pter ( according to hg18-Mar_2006) [Mapping]
Local_order	DAPK1 CTSL1 CTSL3

DNA/RNA



	Shown are the eight exons and seven intron of the human Cathepsin L1 gene. The black boxes correspond to protein coding.

Description	The human Cathepsin L1 gene comprises eight exons and seven introns, and span 5411 bases. The first AUG translation initiation site is located within exon 2. Three spliced variants of hCATL-A have been identified; hCATL-AI, hCATL-AII, hCATL-AIII (Rescheleit et al., 1996; Bakhshi et al., 2001; Aurora et al., 2002; Jean et al., 2002). These spliced forms lack 27 nucleotide (nt), 90 nt and 144 nt from the 3' end of exon 1 respectively and lead to mRNA species that differ in the 5' untranslated regions. However, they are translated into identical proteins. The shorter 5'UTR lack secondary loops and are translated more effectively than hCATL-A (Aurora et al., 2002).
Transcription	One major transcription initiation site is situated at -290 from the starting AUG on the human cDNA sequence (Joseph et al., 1988; Chatham et al., 1993; Bakhshi et al., 2001; Aurora et al., 2002; Jean et al., 2002). This mRNA of 1.7 Kb corresponds to hCATL-A. Another mRNA, hCATL-B, is transcribed from another TATA-less promoter localized within the first intron of hCATL-A and encodes the same cathepsin L protein (Joseph et al., 1988; Bakhshi et al., 2001; Seth, gene 2003). The hCATL-B therefore differs from hCATL-A in the 5' untranslated region (Bakhshi et al., 2001; Jean et al., 2002). The transcription factors NF-Y, SP1 and SP3 have been shown to be responsible for more than 85% of Cathepsin L expression in melanoma cells (Jean et al., 2002). In melanoma and in lymphoma cells, Cathepsin L expression is also regulated by CpG methylation, and gene amplification has been observed in one melanoma cell line (Jean et al., 2006). In tissue culture models, phorbol esters, certain oncogenes such as ras, v-src, SV-40 Large T and raf, cytokines such as IL-1, IL-6 and TNF-alpha, and hypoxia have all been shown to induce cathepsin L expression (Troen et al., 1991; Lemaire et al., 1994; Kakegawa et al., 1995; Lemaire et al., 1997; Heinrich et al., 2000; Gerber et al., 2001; Jean et al., 2008).
Pseudogene	Using the program TBLASTN three pseudogenes, closely related to cathepsin L were identified on chromosome 10 (Rossi et al., 2004).

Protein



	Shown is a schematic representation of the various human cathepsin L isoforms. The full-length protein is composed of a signal peptide (pre), a pro-domain and the mature polypeptide. PF stands for proform, SC for single chain, HC for heavy chain and S correspond to the various short isoforms that are devoid of signal peptide and whose translation is initiated from internal, in-frame, AUGs located within the prodomain coding sequence.

Description	CSTL1 codes for a protein of 333 amino-acids. Like all lysosomal enzymes, cathepsin L is translated as an inactive pre-pro-enzyme. The pre-region, located at the amino terminus of the protein, is a 17 amino-acid signal peptide (or signal sequence). Human cathepsin L is N-glycosylated at Asn 204. This glycosylation event is not required for proper folding of the protein or for its enzymatic activity or stability, but is important for lysosomal targeting (Smith et al., 1989; Kane, 1993). In certain cases, especially in transformed cells, secretion of procathepsin L (MEP) is observed (Gottesman, 1978). The crystal structure of procathepsin L has been resolved (Coulombe et al., 1996). Structurally, like most enzymes from the papain family, the mature cathepsin L consists of two globular regions, the R-domain (right) and L- domain (left) (Turk et al., 1997). These two domains are organized to form an open V-shaped active site cleft. The propiece of cathepsin L can also be separated into two regions. The amino-terminal part, which consists of the first 60 amino acids, is important for proper folding and glycosylation of procathepsin L (Chapman et al., 1997). Expression of the carboxy-terminal part of the prodomain is responsible for the inhibitory role of the propiece, by preventing the entry of the substrate into the active cleft. In order to do so, when the amino-terminus binds to the prodomain binding loop, the carboxy-terminus of the proregion bends over the groove of the active site in the opposite direction that the substrate would have been (Coulombe et al., 1996). The removal of the propiece occurs via an intra and/or inter molecular mechanism as the zymogen reaches the acidic environment of late endosomes or lysosomes (Nishimura et al., 1989; Salminen et al., 1990; Nomura et al., 1997; Ishidoh, et al., 2002). In order for the enzyme to become active, the proregion must be removed (Mason et al., 1992; Ishidoh et al., 1995). Studies have shown that other lysosomal enzymes, such as cathepsin D can also process procathepsin L and be involved in the initial steps of activation (Nishimura et al., 1989). In some cell types, the mature single chain form of cathepsin L is further processed into a two chains, heavy and light, by cleavage of the carboxy-terminus (Mason et al., 1985; Gal et al., 1986; Erickson, 1989). The optimal activity of mature cathepsin L requires a slightly acidic pH and a reducing environment which permits the active cysteine to be oxidized. The maximal activity of cathepsin L, using small synthetic peptides as substrates is at pH 5.5. The enzyme is most stable between pH 4.5 and 5.5. Like all cysteine proteases, the active site of cathepsin L is composed of a reactive cysteine (Cys 25), and a histidine (His 159). In the active form, both residues are charged, forming a thiolate-imidazolium ion pair (McGrath, 1999). Cathepsin L prefers a hydrophobic residue (mainly L/I) in the P2 position (cleavage occurs between residues P1 and P1') (Chapman et al., 1997). In addition, a shorter isoform of Cathepsin L has been detected. Translation at downstream, in-frame, AUGs is responsible for generating a protein that is devoid of a signal peptide which cannot be routed to the endoplasmic reticulum (Goulet et al., 2004; Goulet et al., 2007).
Localisation	Cathepsin L is ubiquitously expressed. It is generally localized to the endosomes/lysosomes or secreted. Recently, various groups have reported the presence of Cathepsin L in the nucleus and the cytoplasm in various cell types (Goulet et al., 2004; Bulynko et al., 2006; Varanou et al., 2006; Sever et al., 2007; Duncan et al., 2008). Moreover, in neuroendocrine chromaffin cell types, Cathepsin L is detected in regulatory secretory vesicules (Yasothornsrikul et al., 2003).
Function	Cathepsin L is a lysosomal enzyme originally thought to be involved in terminal protein degradation only. However, knockout mice showed that terminal protein degradation was not the work of a single cathepsin, as none of these mice had defects in protein degradation. The various phenotypes of these mice rather suggested that this protease has other specific biological roles. One knockout was generated, and two mice with natural mutations within the cathepsin L gene were also identified, Furless and Nackt. The furless mice possess a G-to-A mutation, which substitute an arginine for a glycine at position 149 of the cathepsin L protein sequence, resulting in an inactive enzyme (Roth et al., 2000). The nackt mice display a deletion in the cathepsin L gene, preventing the generation of any functional protein (Benavides et al., 2002). These three animal phenotypes have revealed that Cathepsin L plays a role in various physiological events in different tissues. For example, Cathepsin L is important for epidermal homeostasis, regulation of the hair cycle, control of keratinocyte proliferation, MHC class-II mediated antigen presentation and selection of CD4+ T cells in cortical epithelial cells of the thymus (Nakagawa et al., 1998; Roth et al., 2000; Benavides et al., 2002; Reinheckel et al., 2005). Cathepsin L expression in thymocytes has been shown to be essential for natural killer cell development (Honey et al., 2002). Knockout mice models have demonstrated that Cathepsin L directly participates in atherosclerosis and in neovascularisation induced by endothelial progenitor cells (Maehr et al., 2005; Urbich et al., 2005; Kitamoto et al., 2007). These knockout mice have been observed to develop heart disease similar to human dilated cardiomyopathy (Stypmann et al., 2002). In general, pups lacking cathepsin L also have a slightly higher mortality upon weaning than their littermates (Reinheckel et al., 2001). Cathepsin L is responsible for the processing of viral proteins (Chandran et al., 2005; Pager et al., 2005; Kaletsky et al., 2007; Bosch et al., 2008) and the generation of neuropeptides and thyroid hormone (Funkelstein et al., 2008; Funkelstein et al., 2008). Cathepsin L activity is responsible for adipogenesis and glucose tolerance by degrading matrix fibronectin and processing the insulin receptor and IGF-1R beta (Yang et al., 2007). It is involved in intestinal epithelial cell polarization and differentiation (Boudreau et al., 2007) and in proteinuric kidney disease (Sever et al., 2007). Nuclear Cathepsin L was shown to proteolytically process a transcription factor during the G1/S progression of the cell cycle (Goulet et al., 2004) and histone H3 during mouse embryonic stem cell differentiation (Duncan et al., 2008). The landscape modifications of the histone on the Y chromosome and pericentromeric heterochromatine are stabilized by Cathepsin L (Bulynko et al., 2006). The role of Cathepsin L in cancer has been studied extensively. Secreted Cathepsin L degrades basal membrane and extracellular matrix therefore could increase the development of metastases. Intracellular cathepsin L activity can lead to activation of oncogenes or inactivation of tumor suppressors (Goulet et al., 2007). A recent paper also indicate that Cathepsin L plays a role in drug resistance (Zheng et al., 2008).
Homology	Human Cathepsin L1 belongs to the papain superfamily. Cathepsin L2 (formerly called Cathepsin V) originated from ancestral Cathepsin L as they share 77% amino-acids identity. Moreover, both are similar to mouse cathepsin L (72% and 75% respectively) and other mammals (Itoh et al., 1999).

Mutations

Note	Not determined.

Implicated in

Entity	Various cancers
Oncogenesis	Cathepsin L was initially identified as the major excreted protein (MEP) secreted from transformed fibroblastic cells (Gottesman, 1978; Troen et al., 1987; Troen et al., 1988). Oncogenic signals such as Ras, Raf, v-Src, fos, SV40 Large T as well as tumor promoters like phorbol ester can induce MEP expression and secretion (Joseph et al., 1987; Taniguchi et al., 1990; Troen et al., 1991; Lemaire et al., 1994; Heinrich et al., 2000). Moreover, cathepsin L secretion correlated with the metastatic potential of transformed cell lines (Denhardt et al., 1987; Chambers et al., 1992). Increased cathepsin L activity and secretion has been observed in many human cancers (Watanabe et al., 1987; Sheahan et al., 1989; Chauhan et al., 1991; Heidtmann et al., 1993; Nishida et al., 1995; Plebani et al., 1995; Park et al., 1996; Shuja et al., 1996; Sivaparvathi et al., 1996; Leto et al., 1997; Kim et al., 1998; Dohchin et al., 2000). Various reports also suggested that cathepsin L levels could be used as a potential indicator of tumor aggressiveness and metastasis (Thomssen et al., 1995; Park et al., 1996). Increased nuclear Cathepsin L expression and activity was recently found in various cancer cells, suggesting a different mechanism of cellular transformation (Goulet et al., 2007). Therefore, although the association of cathepsin L and cancer is well established, its specific roles have not yet been fully elucidated.

Entity	Breast cancer
Prognosis	In breast cancer, numerous studies have indicated that secreted cathepsin L could be a strong and independent prognostic factor, with a strength similar to lymph node status and grading (Castiglioni et al., 1994; Thomssen et al., 1995; Duffy, 1996; Foekens et al., 1998; Thomssen et al., 1998; Harbeck et al., 2000; Harbeck et al., 2001; Levicar et al., 2002). Cathepsin L expression could also predict response to adjuvant chemotherapy (Jagodic et al., 2005).

Entity	Gastric carcinoma
Prognosis	Cathepsin L expression correlates with an early event in gastric carcinogenesis and with depth of invasion in early stage of gastric carcinoma. Higher expression is associated with worst prognosis (Plebani et al., 1995; Farinati et al., 1996; Dohchin et al., 2000).

Entity	Skin cancer
Prognosis	Higher concentration of Cathepsin L in early primary melanomas correlates with poor prognosis and indicate possible early metastasis spread (Stabuc et al., 2006). In malignant cells of squamous cell carcinoma, Cathepsin L is mainly overexpressed at the periphery of the tumor. Cathepsin L is also overexpressed in various inflammatory skin diseases such as psoriasis and atopic eczema (Bylaite et al., 2006).

Entity	Ovarian cancer
Prognosis	Cathepsin L expression is increased in ovarian cancer sample as well as in the serum of patients with ovarian cancer. Serum levels of Cathepsin L could be used in early detection of ovarian cancers (Nishida et al., 1995).

Entity	Bladder cancer
Prognosis	Urinary Cathepsin L is an independent predictor of bladder urothelial cell cancer and invasiveness (Svatek et al., 2008).

Entity	Brain cancer (neuroblastoma)
Prognosis	Cathepsin L has no prognostic value in glioma, but its expression is increased in tumor cells (Strojnik et al., 2005). In invasive benign meningioma and pituitary adenomas, Cathepesin L levels are also higher (Strojnik et al., 2001; Strojnik et al., 2005).

Entity	Pancreatic adenocarcinoma
Prognosis	Cathepsin L is a strong independent prognostic marker in resectable cancers (Niedergethmann et al., 2004).

External links

	Nomenclature
HGNC (Hugo)	CTSL1 2537
Entrez_Gene (NCBI)	CTSL1 1514 cathepsin L1
	Cards
Atlas	CTSL1ID40208ch9q21
GeneCards (Weizmann)	CTSL1
Ensembl (Hinxton)	ENSG00000135047 [Gene_View] CTSL1 [Vega]
AceView (NCBI)	CTSL1
Genatlas (Paris)	CTSL1
euGene (Indiana)	1514
SOURCE (Stanford)	NM_001912 NM_145918
Gene Expression (Array Express)	ENSG00000135047
	Genomic and cartography
GoldenPath (UCSC)	CTSL1 - 9q21.33 chr9:89530794-89536202 + 9q21-q22 [Description] (hg18-Mar_2006)
Ensembl	CTSL1 - 9q21-q22 [CytoView]
Mapping of homologs : NCBI	CTSL1 [Mapview]
OMIM	116880
	Gene and transcription
Gene : Genbank (Entrez)	AF217997 AF304301 AF467444 AK055599 AK075100
Reference sequence (RefSeq transcript) :SRS	NM_001912 NM_145918
Reference transcript : Entrez	NM_001912 NM_145918
RefSeq genomic : SRS	AC_000052 AC_000141 NC_000009 NT_008470 NW_001839222 NW_924484
RefSeq genomic : Entrez	AC_000052 AC_000141 NC_000009 NT_008470 NW_001839222 NW_924484
Consensus coding sequences : CCDS NCBI	CTSL1
Cluster EST : Unigene	Hs.418123 [ SRS ] Hs.418123 [ NCBI ]
Alternative Splicing : Fast-db (Paris)	10357
	Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProt	P07711 (SRS) P07711 (Expasy) P07711 (Uniprot)
With graphics : InterPro	P07711
Splice isoforms : VarSplice FASTA	P07711(VarSplice FASTA)
Domaine pattern : Prosite (SRS)	THIOL_PROTEASE_ASN (PS00640) THIOL_PROTEASE_CYS (PS00139) THIOL_PROTEASE_HIS (PS00639)
Domain pattern : Prosite (Expaxy)	THIOL_PROTEASE_ASN (PS00640) THIOL_PROTEASE_CYS (PS00139) THIOL_PROTEASE_HIS (PS00639)
Domains : Interpro (SRS)	Pept_cys_AS Peptidase_C1A Peptidase_C1A_C Prot_inhib_I29
Domains : Interpro (EBI)	Pept_cys_AS Peptidase_C1A Peptidase_C1A_C Prot_inhib_I29
Related proteins : CluSTr	P07711
Domain families : Pfam SRS	Inhibitor_I29 (PF08246) Peptidase_C1 (PF00112)
Domain families : Pfam Sanger	Inhibitor_I29 (PF08246) Peptidase_C1 (PF00112)
Domain families : Pfam NCBI	pfam08246 pfam00112
Domain families : Smart EMBL	Inhibitor_I29 (SM00848) Pept_C1 (SM00645)
Blocks (Seattle)	P07711
Crystal structure of protein : PDB SRS	1CJL 1CS8 1ICF 1MHW 2NQD 2VHS 3BC3 3H89 3H8B 3H8C 3HHA 3HWN
Crystal structure of protein : PDBSum	1CJL 1CS8 1ICF 1MHW 2NQD 2VHS 3BC3 3H89 3H8B 3H8C 3HHA 3HWN
Crystal structure of protein : IMB	1CJL 1CS8 1ICF 1MHW 2NQD 2VHS 3BC3 3H89 3H8B 3H8C 3HHA 3HWN
Crystal structure of protein : PDB RSDB	1CJL 1CS8 1ICF 1MHW 2NQD 2VHS 3BC3 3H89 3H8B 3H8C 3HHA 3HWN
HPRD	00293
	Protein Interaction databases
DIP (DOE-UCLA)	P07711
IntAct (EBI)	P07711
	Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBI	CTSL1
SNP : GeneSNP Utah	CTSL1
SNP : HGBase	CTSL1
Genetic variants : HAPMAP	CTSL1
Somatic Mutations in Cancer : COSMIC	CTSL1
Mutations and Diseases : HGMD	CTSL1
Hereditary diseases : OMIM	116880
Hereditary diseases : GENETests	116880
Diseases : Genetic Association	CTSL1
	General knowledge
Homologs : HomoloGene	CTSL1
Homology/Alignments : Family Browser UCSC	CTSL1
Phylogenetic Trees/Animal Genes : TreeFam	CTSL1
Catalytic activity : Enzyme	3.4.22.15 [ Enzyme-Expasy ] 3.4.22.15 [ Enzyme-SRS ] 3.4.22.15 [ IntEnz-EBI ] 3.4.22.15 [ BRENDA ] 3.4.22.15 [ KEGG ]
Chemical/Protein Interactions : CTD	1514
Keywords Ontology : AmiGO	aminopeptidase activity cysteine-type endopeptidase activity extracellular region soluble fraction lysosome proteolysis peptidase activity kininogen binding peptide binding
Keywords Ontology : EGO-EBI	aminopeptidase activity cysteine-type endopeptidase activity extracellular region soluble fraction lysosome proteolysis peptidase activity kininogen binding peptide binding
Pathways : BIOCARTA
Pathways : KEGG	Antigen processing and presentation
	Other databases
	Probes
Probes : Imagenes	CTSL1 Related clones (RZPD - Berlin)
	Literature
PubMed	95 Pubmed reference(s) in Entrez
PubGene	CTSL1

Bibliography

Transformation-dependent secretion of a low molecular weight protein by murine fibroblasts.

Gottesman MM.

Proc Natl Acad Sci U S A. 1978 Jun;75(6):2767-71.

PMID 351614

Human liver cathepsin L.

Mason RW, Green GD, Barrett AJ.

Biochem J. 1985 Feb 15;226(1):233-41.

PMID 3977867

The major excreted protein (MEP) of transformed mouse cells and cathepsin L have similar protease specificity.

Gal S, Gottesman MM.

Biochem Biophys Res Commun. 1986 Aug 29;139(1):156-62.

PMID 3533059

Cysteine proteinase cathepsin L expression correlates closely with the metastatic potential of H-ras-transformed murine fibroblasts.

Denhardt DT, Greenberg AH, Egan SE, Hamilton RT, Wright JA.

Oncogene. 1987;2(1):55-9.

PMID 3438085

The major ras induced protein in NIH3T3 cells is cathepsin L.

Joseph L, Lapid S, Sukhatme V.

Nucleic Acids Res. 1987 Apr 10;15(7):3186.

PMID 3550705

Sequence and expression of the cDNA for MEP (major excreted protein), a transformation-regulated secreted cathepsin.

Troen BR, Gal S, Gottesman MM.

Biochem J. 1987 Sep 15;246(3):731-5.

PMID 3689328

Elevation of tissue cathepsin B and L activities in gastric cancer.

Watanabe M, Higashi T, Hashimoto M, Tomoda I, Tominaga S, Hashimoto N, Morimoto S, Yamauchi Y, Nakatsukasa H, Kobayashi M, et al.

Hepatogastroenterology. 1987 Jun;34(3):120-2.

PMID 3610018

Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. An abundant transcript induced by transformation of fibroblasts.

Joseph LJ, Chang LC, Stamenkovich D, Sukhatme VP.

J Clin Invest. 1988 May;81(5):1621-9.

PMID 2835398

Cloning and expression of the gene for the major excreted protein of transformed mouse fibroblasts. A secreted lysosomal protease regulated by transformation.

Troen BR, Ascherman D, Atlas D, Gottesman MM.

J Biol Chem. 1988 Jan 5;263(1):254-61.

PMID 2826441

Biosynthesis of lysosomal endopeptidases.

Erickson AH.

J Cell Biochem. 1989 May;40(1):31-41.

PMID 2663888

Evidence that aspartic proteinase is involved in the proteolytic processing event of procathepsin L in lysosomes.

Nishimura Y, Kawabata T, Furuno K, Kato K.

Arch Biochem Biophys. 1989 Jun;271(2):400-6.

PMID 2658811

Cysteine protease activities and tumor development in human colorectal carcinoma.

Sheahan K, Shuja S, Murnane MJ.

Cancer Res. 1989 Jul 15;49(14):3809-14.

PMID 2544258

Glycosylation of procathepsin L does not account for species molecular-mass differences and is not required for proteolytic activity.

Smith SM, Kane SE, Gal S, Mason RW, Gottesman MM.

Biochem J. 1989 Sep 15;262(3):931-8.

PMID 2480110

Inhibitor studies indicate that active cathepsin L is probably essential to its own processing in cultured fibroblasts.

Salminen A, Gottesman MM.

Biochem J. 1990 Nov 15;272(1):39-44.

PMID 2264836

Augmented excretion of procathepsin L of a fos-transferred highly metastatic rat cell line.

Taniguchi S, Nishimura Y, Takahashi T, Baba T, Kato K.

Biochem Biophys Res Commun. 1990 Apr 30;168(2):520-6.

PMID 2185753

Expression of cathepsin L in human tumors.

Chauhan SS, Goldstein LJ, Gottesman MM.

Cancer Res. 1991 Mar 1;51(5):1478-81.

PMID 1997186

Downstream sequences mediate induction of the mouse cathepsin L promoter by phorbol esters.

Troen BR, Chauhan SS, Ray D, Gottesman MM.

Cell Growth Differ. 1991 Jan;2(1):23-31.

PMID 1848774

Increased expression of cathepsins L and B and decreased activity of their inhibitors in metastatic, ras-transformed NIH 3T3 cells.

Chambers AF, Colella R, Denhardt DT, Wilson SM.

Mol Carcinog. 1992;5(3):238-45.

PMID 1586450

Surface activation of pro-cathepsin L.

Mason RW, Massey SD.

Biochem Biophys Res Commun. 1992 Dec 30;189(3):1659-66.

PMID 1482371

Cloning, genomic organization, and chromosomal localization of human cathepsin L.

Chauhan SS, Popescu NC, Ray D, Fleischmann R, Gottesman MM, Troen BR.

J Biol Chem. 1993 Jan 15;268(2):1039-45.

PMID 8419312

Secretion of a latent, acid activatable cathepsin L precursor by human non-small cell lung cancer cell lines.

Heidtmann HH, Salge U, Havemann K, Kirschke H, Wiederanders B.

Oncol Res. 1993;5(10-11):441-51.

PMID 8054705

Mouse procathepsin L lacking a functional glycosylation site is properly folded, stable, and secreted by NIH 3T3 cells.

Kane SE.

J Biol Chem. 1993 May 25;268(15):11456-62.

PMID 8496193

Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer.

Castiglioni T, Merino MJ, Elsner B, Lah TT, Sloane BF, Emmert-Buck MR.

Hum Pathol. 1994 Sep;25(9):857-62.

PMID 8088759

Synovial fibroblast-like cell transfection with the SV40 large T antigen induces a transformed phenotype and permits transient tumor formation in immunodeficient mice.

Lemaire R, Flipo RM, Monte D, Dupressoir T, Duquesnoy B, Cesbron JY, Janin A, Capron A, Lafyatis R.

J Rheumatol. 1994 Aug;21(8):1409-19.

PMID 7983639

Procathepsin L degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro.

Ishidoh K, Kominami E.

Biochem Biophys Res Commun. 1995 Dec 14;217(2):624-31.

PMID 7503744

Secretion and processing mechanisms of procathepsin L in bone resorption.

Kakegawa H, Tagami K, Ohba Y, Sumitani K, Kawata T, Katunuma N.

FEBS Lett. 1995 Aug 14;370(1-2):78-82.

PMID 7649308

Increased cathepsin L levels in serum in some patients with ovarian cancer: comparison with CA125 and CA72-4.

Nishida Y, Kohno K, Kawamata T, Morimitsu K, Kuwano M, Miyakawa I.

Gynecol Oncol. 1995 Mar;56(3):357-61.

PMID 7705668

Cysteine and serine proteases in gastric cancer.

Plebani M, Herszenyi L, Cardin R, Roveroni G, Carraro P, Paoli MD, Rugge M, Grigioni WF, Nitti D, Naccarato R, et al.

Cancer. 1995 Aug 1;76(3):367-75.

PMID 8625115

Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer.

Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Janicke F, Graeff H.

Clin Cancer Res. 1995 Jul;1(7):741-6.

PMID 9816040

Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.

Coulombe R, Grochulski P, Sivaraman J, Menard R, Mort JS, Cygler M.

EMBO J. 1996 Oct 15;15(20):5492-503.

PMID 8896443

Proteases as prognostic markers in cancer.

Duffy MJ.

Clin Cancer Res. 1996 Apr;2(4):613-8.

PMID 9816210

Increased levels of cathepsin B and L, urokinase-type plasminogen activator and its inhibitor type-1 as an early event in gastric carcinogenesis.

Farinati F, Herszenyi L, Plebani M, Carraro P, De Paoli M, Cardin R, Roveroni G, Rugge M, Nitti D, Grigioni WF, D'Errico A, Naccarato R.

Carcinogenesis. 1996 Dec;17(12):2581-7.

PMID 9006092

Enhanced expression of cathepsin L in metastatic bone tumors.

Park IC, Lee SY, Jeon DG, Lee JS, Hwang CS, Hwang BG, Lee SH, Hong WS, Hong SI.

J Korean Med Sci. 1996 Apr;11(2):144-8.

PMID 8835762

Sequence analysis and distribution of two new human cathepsin L splice variants.

Rescheleit DK, Rommerskirch WJ, Wiederanders B.

FEBS Lett. 1996 Oct 7;394(3):345-8.

PMID 8830671

Marked increases in cathepsin B and L activities distinguish papillary carcinoma of the thyroid from normal thyroid or thyroid with non-neoplastic disease.

Shuja S, Murnane MJ.

Int J Cancer. 1996 May 16;66(4):420-6.

PMID 8635854

Expression and immunohistochemical localization of cathepsin L during the progression of human gliomas.

Sivaparvathi M, Yamamoto M, Nicolson GL, Gokaslan ZL, Fuller GN, Liotta LA, Sawaya R, Rao JS.

Clin Exp Metastasis. 1996 Jan;14(1):27-34.

PMID 8521613

Emerging roles for cysteine proteases in human biology.

Chapman HA, Riese RJ, Shi GP.

Annu Rev Physiol. 1997;59:63-88.

PMID 9074757

Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibroblast-like cells.

Lemaire R, Huet G, Zerimech F, Grard G, Fontaine C, Duquesnoy B, Flipo RM.

Br J Rheumatol. 1997 Jul;36(7):735-43.

PMID 9255106

Lysosomal cathepsins B and L and Stefin A blood levels in patients with hepatocellular carcinoma and/or liver cirrhosis: potential clinical implications.

Leto G, Tumminello FM, Pizzolanti G, Montalto G, Soresi M, Gebbia N.

Oncology. 1997 Jan-Feb;54(1):79-83.

PMID 8978598

Processing properties of recombinant human procathepsin L.

Nomura T, Fujisawa Y.

Biochem Biophys Res Commun. 1997 Jan 3;230(1):143-6.

PMID 9020032

Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors.

Turk B, Turk V, Turk D.

Biol Chem. 1997 Mar-Apr;378(3-4):141-50.

PMID 9165064

Prognostic significance of cathepsins B and L in primary human breast cancer.

Foekens JA, Kos J, Peters HA, Krasovec M, Look MP, Cimerman N, Meijer-van Gelder ME, Henzen-Logmans SC, van Putten WL, Klijn JG.

J Clin Oncol. 1998 Mar;16(3):1013-21.

PMID 9508185

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Science. 1998 Apr 17;280(5362):450-3.

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DNA Res. 1999 Apr 30;6(2):137-40.

PMID 10382972

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Annu Rev Biophys Biomol Struct. 1999;28:181-204.

PMID 10410800

Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma.

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Cancer. 2000 Aug 1;89(3):482-7.

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Int J Biol Markers. 2000 Jan-Mar;15(1):79-83.

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J Mol Med. 2000;78(7):380-8.

PMID 11043381

Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling.

Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, Schmidt P, Schmahl W, Scherer J, Anton-Lamprecht I, Von Figura K, Paus R, Peters C.

FASEB J. 2000 Oct;14(13):2075-86.

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Gene. 2001 Sep 5;275(1):93-101.

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J Interferon Cytokine Res. 2001 Jan;21(1):11-9.

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Clin Cancer Res. 2001 Sep;7(9):2757-64.

PMID 11555589

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Reinheckel T, Deussing J, Roth W, Peters C.

Biol Chem. 2001 May;382(5):735-41.

PMID 11517926

Cathepsins B and L are markers for clinically invasive types of meningiomas.

Strojnik T, Zidanik B, Kos J, Lah TT.

Neurosurgery. 2001 Mar;48(3):598-605.

PMID 11270551

Identification and characterization of a novel human cathepsin L splice variant.

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Gene. 2002 Jun 26;293(1-2):123-31.

PMID 12137950

Impaired hair follicle morphogenesis and cycling with abnormal epidermal differentiation in nackt mice, a cathepsin L-deficient mutation.

Benavides F, Starost MF, Flores M, Gimenez-Conti IB, Guenet JL, Conti CJ.

Am J Pathol. 2002 Aug;161(2):693-703.

PMID 12163394

Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands.

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J Exp Med. 2002 May 20;195(10):1349-58.

PMID 12021314

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Biol Chem. 2002 Dec;383(12):1827-31.

PMID 12553719

Characterization of human cathepsin L promoter and identification of binding sites for NF-Y, Sp1 and Sp3 that are essential for its activity.

Jean D, Guillaume N, Frade R.

Biochem J. 2002 Jan 1;361(Pt 1):173-84.

PMID 11742542

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Cancer Detect Prev. 2002;26(1):42-9.

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Stypmann J, Glaser K, Roth W, Tobin DJ, Petermann I, Matthias R, Monnig G, Haverkamp W, Breithardt G, Schmahl W, Peters C, Reinheckel T.

Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6234-9. Epub 2002 Apr 23.

PMID 11972068

Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter.

Yasothornsrikul S, Greenbaum D, Medzihradszky KF, Toneff T, Bundey R, Miller R, Schilling B, Petermann I, Dehnert J, Logvinova A, Goldsmith P, Neveu JM, Lane WS, Gibson B, Reinheckel T, Peters C, Bogyo M, Hook V.

Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9590-5. Epub 2003 Jul 17.

PMID 12869695

A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor.

Goulet B, Baruch A, Moon NS, Poirier M, Sansregret LL, Erickson A, Bogyo M, Nepveu A.

Mol Cell. 2004 Apr 23;14(2):207-19.

PMID 15099520

Prognostic impact of cysteine proteases cathepsin B and cathepsin L in pancreatic adenocarcinoma.

Niedergethmann M, Wostbrock B, Sturm JW, Willeke F, Post S, Hildenbrand R.

Pancreas. 2004 Oct;29(3):204-11.

PMID 15367886

Comprehensive search for cysteine cathepsins in the human genome.

Rossi A, Deveraux Q, Turk B, Sali A.

Biol Chem. 2004 May;385(5):363-72.

PMID 15195995

Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection.

Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM.

Science. 2005 Jun 10;308(5728):1643-5. Epub 2005 Apr 14.

PMID 15831716

Prognostic and predictive value of cathepsins D and L in operable breast cancer patients.

Jagodic M, Vrhovec I, Borstnar S, Cufer T.

Neoplasma. 2005;52(1):1-9.

PMID 15739019

Cathepsin L is essential for onset of autoimmune diabetes in NOD mice.

Maehr R, Mintern JD, Herman AE, Lennon-Dumenil AM, Mathis D, Benoist C, Ploegh HL.

J Clin Invest. 2005 Oct;115(10):2934-43. Epub 2005 Sep 22.

PMID 16184198

Cathepsin L is involved in proteolytic processing of the Hendra virus fusion protein.

Pager CT, Dutch RE.

J Virol. 2005 Oct;79(20):12714-20.

PMID 16188974

The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling.

Reinheckel T, Hagemann S, Dollwet-Mack S, Martinez E, Lohmuller T, Zlatkovic G, Tobin DJ, Maas-Szabowski N, Peters C.

J Cell Sci. 2005 Aug 1;118(Pt 15):3387-95.

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Cancer Detect Prev. 2005;29(5):448-55. Epub 2005 Sep 23.

PMID 16183211

Immunohistochemical staining of cathepsins B, L and stefin A in human hypophysis and pituitary adenomas.

Strojnik T, Lah TT, Zidanik B.

Anticancer Res. 2005 Jan-Feb;25(1B):587-94.

PMID 15816632

Cathepsin L is required for endothelial progenitor cell-induced neovascularization.

Urbich C, Heeschen C, Aicher A, Sasaki K, Bruhl T, Farhadi MR, Vajkoczy P, Hofmann WK, Peters C, Pennacchio LA, Abolmaali ND, Chavakis E, Reinheckel T, Zeiher AM, Dimmeler S.

Nat Med. 2005 Feb;11(2):206-13. Epub 2005 Jan 23.

PMID 15665831

Cathepsin L stabilizes the histone modification landscape on the Y chromosome and pericentromeric heterochromatin.

Bulynko YA, Hsing LC, Mason RW, Tremethick DJ, Grigoryev SA.

Mol Cell Biol. 2006 Jun;26(11):4172-84.

PMID 16705169

Expression of cathepsin L and its inhibitor hurpin in inflammatory and neoplastic skin diseases.

Bylaite M, Moussali H, Marciukaitiene I, Ruzicka T, Walz M.

Exp Dermatol. 2006 Feb;15(2):110-8.

PMID 16433682

Expression of cathepsin L in human tumor cells is under the control of distinct regulatory mechanisms.

Jean D, Rousselet N, Frade R.

Oncogene. 2006 Mar 9;25(10):1474-84.

PMID 16261157

Expression and prognostic significance of Cathepsin L in early cutaneous malignant melanoma.

Stabuc B, Mrevlje Z, Markovic J, Stabuc-Silih M.

Neoplasma. 2006;53(3):259-62.

PMID 16652198

The importance of cysteine cathepsin proteases for placental development.

Varanou A, Withington SL, Lakasing L, Williamson C, Burton GJ, Hemberger M.

J Mol Med. 2006 Apr;84(4):305-17. Epub 2006 Jan 27.

PMID 16440214

Loss of cathepsin L activity promotes claudin-1 overexpression and intestinal neoplasia.

Boudreau F, Lussier CR, Mongrain S, Darsigny M, Drouin JL, Doyon G, Suh ER, Beaulieu JF, Rivard N, Perreault N.

FASEB J. 2007 Dec;21(14):3853-65. Epub 2007 Jul 10.

PMID 17622569

Increased expression and activity of nuclear cathepsin L in cancer cells suggests a novel mechanism of cell transformation.

Goulet B, Sansregret L, Leduy L, Bogyo M, Weber E, Chauhan SS, Nepveu A.

Mol Cancer Res. 2007 Sep;5(9):899-907.

PMID 17855659

Proteolysis of the Ebola virus glycoproteins enhances virus binding and infectivity.

Kaletsky RL, Simmons G, Bates P.

J Virol. 2007 Dec;81(24):13378-84. Epub 2007 Oct 10.

PMID 17928356

Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice.

Kitamoto S, Sukhova GK, Sun J, Yang M, Libby P, Love V, Duramad P, Sun C, Zhang Y, Yang X, Peters C, Shi GP.

Circulation. 2007 Apr 17;115(15):2065-75. Epub 2007 Apr 2.

PMID 17404153

Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease.

Sever S, Altintas MM, Nankoe SR, Moller CC, Ko D, Wei C, Henderson J, del Re EC, Hsing L, Erickson A, Cohen CD, Kretzler M, Kerjaschki D, Rudensky A, Nikolic B, Reiser J.

J Clin Invest. 2007 Aug;117(8):2095-104.

PMID 17671649

Cathepsin L activity controls adipogenesis and glucose tolerance.

Yang M, Zhang Y, Pan J, Sun J, Liu J, Libby P, Sukhova GK, Doria A, Katunuma N, Peroni OD, Guerre-Millo M, Kahn BB, Clement K, Shi GP.

Nat Cell Biol. 2007 Aug;9(8):970-7. Epub 2007 Jul 22.

PMID 17643114

Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide.

Bosch BJ, Bartelink W, Rottier PJ.

J Virol. 2008 Sep;82(17):8887-90. Epub 2008 Jun 18.

PMID 18562523

Cathepsin L proteolytically processes histone H3 during mouse embryonic stem cell differentiation.

Duncan EM, Muratore-Schroeder TL, Cook RG, Garcia BA, Shabanowitz J, Hunt DF, Allis CD.

Cell. 2008 Oct 17;135(2):284-94.

PMID 18957203

Cathepsin L participates in the production of neuropeptide Y in secretory vesicles, demonstrated by protease gene knockout and expression.

Funkelstein L, Toneff T, Hwang SR, Reinheckel T, Peters C, Hook V.

J Neurochem. 2008 Jul;106(1):384-91. Epub 2008 Jul 1.

PMID 18410501

Major role of cathepsin L for producing the peptide hormones ACTH, beta -endorphin, and alpha -MSH, illustrated by protease gene knockout and expression.

Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V.

J Biol Chem. 2008 Dec 19;283(51):35652-9. Epub 2008 Oct 10.

PMID 18849346

Cathepsin L expression is up-regulated by hypoxia in human melanoma cells: role of its 5'-untranslated region.

Jean D, Rousselet N, Frade R.

Biochem J. 2008 Jul 1;413(1):125-34.

PMID 18366346

Role of urinary cathepsin B and L in the detection of bladder urothelial cell carcinoma.

Svatek RS, Karam J, Karakiewicz PI, Gallina A, Casella R, Roehrborn CG, Shariat SF.

J Urol. 2008 Feb;179(2):478-84; discussion 484.

PMID 18076936

Cathepsin L Inhibition Suppresses Drug Resistance in Vitro and in Vivo: a Putative Mechanism.

Zheng X, Chu F, Chou PM, Gallati C, Dier U, Mirkin BL, Mousa SA, Rebbaa A.

Am J Physiol Cell Physiol. 2009 Jan;296(1):C65-74. Epub 2008 Oct 29.

PMID 18971393

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Contributor(s)

Written	01-2009	Brigitte Goulet, Alain Nepveu
		Cancer research Laboratory Program, London Regional Cancer Program at London Health Science Centre and the University of Western Ontario, London, Canada (BG); Department of Biochemistry, Goodman Cancer Centre, McGill University, Montreal, Canada (AN)

Citation
This paper should be referenced as such :
Goulet B, Nepveu A . CTSL1 (cathepsin L1). Atlas Genet Cytogenet Oncol Haematol. January 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/CTSL1ID40208ch9q21.html

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