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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CTHRC1 (Collagen Triple Helix Repeat Containing 1) Renee J LeClair, Tahir Durmus, Volkhard Lindner Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA (RJLC, TD, VL) Published in Atlas Database: November 2008 Online updated version : http://AtlasGeneticsOncology.org/Genes/CTHRC1ID40193ch8q22.html DOI: 10.4267/2042/44579 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology the inner ear has been reported in a Cthrc1 mutant mouse with a beta-galactosidase expression construct replacing the first exon of Cthrc1. Expression of Cthrc1 is increased in fibroblasts and chondrocytic cells in response to TGF-beta family members including BMP4, BMP2 and TGF-beta. Cthrc1 is also upregulated during tumorigenesis and metastasis; its role during this process is unknown. Identity Other names: NMTC1 HGNC (Hugo): CTHRC1 Location: 8q22.3 DNA/RNA Description Localisation CTHRC1 spans 4 exons and is a 1.2 kb transcript. CTHRC1 has a signal peptide that targets it to the ERGolgi pathway for secretion. In the extracellular environment the molecule is sensitive to cleavage by proteases such as plasmin. While CTHRC1 is abundant in cartilage matrix, the CTHRC1 protein has been observed in the cytoplasm of select cell types such as certain neuronal populations and parafollicular cells of the thyroid gland despite the presence of the signal peptide. Protein Description Collagen Triple Helix Repeat Containing-1, CTHRC1, is a 30kDa secreted protein that has the ability to inhibit collagen matrix synthesis. CTHRC1 is glycosylated and retains a signal sequence consistent with it being secreted from the cell. Activity of the protein is reliant on removal of the propeptide and while CTHRC1 does not contain a predictable consensus propeptide cleavage site, there is direct evidence demonstrating the ability of plasmin to cleave the secreted protein at residues E46 and R96. Function CTHRC1 has been linked to major signaling pathways such as Wnt and TGF-beta. The ability of CTHRC1 to inhibit TGF-beta signaling via a reduction in Smad 2/Smad 3 phosphorylation has been demonstrated both in vivo and in vitro models. This inhibition translates into a reduction in collagen type I deposition during vascular remodeling. Characterization of Cthrc1 deficient mice indicated that the gene is not essential for normal development. Evidence from in vitro studies suggested that Cthrc1 may play a role in the Planar Cell Polarity (PCP) pathway of non-canonical Wnt signaling. Combinatorial mutations in both Cthrc1 alleles and a single allele of Vangl2, a gene previously shown to be involved in noncanonical Wnt signaling, resulted in animals lacking proper orientation of inner and outer ear hair cells. Further biochemical analysis showed Expression The expression patterns of Cthrc1 during murine embryonic development and in postnatal tissues have been characterized with in situ hybridization and immunohistochemistry (see Durmus et al., 2007 for a complete review). Cthrc1 expression levels are induced in the adventitia and intimal smooth muscle after balloon catheter injury of arteries. Additionally, Cthrc1 is highly expressed in cartilage and developing bones as well as in myofibroblasts during skin wound healing. Indirect evidence for the expression of Cthrc1 by hair cells of Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10) 719 CTHRC1 (Collagen Triple Helix Repeat Containing 1) LeClair R, et al. Cthrc1 associated with several of the Frizzled family of receptors suggesting it may stabilize the receptor ligand complex on the cell surface. Cthrc1 deficient mice also demonstrated a reduction in bone density that was attributable to a reduction in osteoblast number and coverage. Mechanistically, it is unclear how this occurs but was shown to be due to a reduction in osteoblast proliferation rather than an increase in osteoclasts. inhibits collagen expression and promotes cell migration. Circ Res. 2005 Feb 4;96(2):261-8 Homology LeClair R, Lindner V. The role of collagen triple helix repeat containing 1 in injured arteries, collagen expression, and transforming growth factor beta signaling. Trends Cardiovasc Med. 2007 Aug;17(6):202-5 Durmus T, LeClair RJ, Park KS, Terzic A, Yoon JK, Lindner V. Expression analysis of the novel gene collagen triple helix repeat containing-1 (Cthrc1). Gene Expr Patterns. 2006 Oct;6(8):935-40 Tang L, Dai DL, Su M, Martinka M, Li G, Zhou Y. Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers. Clin Cancer Res. 2006 Jun 15;12(12):3716-22 CTHRC1 is a unique protein, displaying an extremely high level of conservation among vertebrates, but showing very little homology to other currently known proteins. Structurally, it contains a short collagen-like motif similar to the collagen domains present in the C1q/tumor necrosis factor-a-related proteins (CTRPs). Both CTHRC1 and CTRP members share a conserved and post-translationally modified lysine residue present in the collagen domain, but currently there are no data to suggest that the collagen domain of CTHRC1 leads to trimerization. LeClair RJ, Durmus T, Wang Q, Pyagay P, Terzic A, Lindner V. Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation. Circ Res. 2007 Mar 30;100(6):826-33 Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, Hajduch M, Murray P, Kolar Z. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007 Mar 27;7:55 Wu YT, Liu RH, Yang Y, Luo YQ, Rong Y. [Construction of a subtracted cDNA library of chronic intermittent hypoxia rabbit liver by suppression subtractive hybridization]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Dec;32(6):1013-9 Implicated in Breast cancer Kang BY, Tsoi S, Zhu S, Su S, Kay HH. Differential gene expression profiling in HELLP syndrome placentas. Reprod Sci. 2008 Apr;15(3):285-94 Disease Lobular carcinoma and invasive ductal carcinoma. Prognosis Undetermined. Suggested that CTHRC1 expression in these tumors is associated with cancer tissue invasion and metastasis. Kelley MW. Leading Wnt down a PCP path: Cthrc1 acts as a coreceptor in the Wnt-PCP pathway. Dev Cell. 2008 Jul;15(1):7-8 Kimura H, Kwan KM, Zhang Z, Deng JM, Darnay BG, Behringer RR, Nakamura T, de Crombrugghe B, Akiyama H. Cthrc1 is a positive regulator of osteoblastic bone formation. PLoS One. 2008 Sep 9;3(9):e3174 Solid cancers Disease Melanomas, cancers of the rectum, small intestine, colon, liver, lung, ovary, breast, thyroid gland and cervix. Prognosis CTHRC1 is upregulated in solid tumors. Linked expression levels to prognosis is undetermined. Leclair RJ, Wang Q, Benson MA, Prudovsky I, Lindner V. Intracellular localization of Cthrc1 characterizes differentiated smooth muscle. Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1332-8 Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S, Tarui H, Sasaki H. Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell. 2008 Jul;15(1):23-36 References This article should be referenced as such: Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L, Friesel RE, Lindner V. Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, LeClair R, Durmus T, Lindner V. CTHRC1 (Collagen Triple Helix Repeat Containing 1). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10):719-720. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10) 720