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CTHRC1 (Collagen Triple Helix Repeat Containing 1)

Identity

Other namesNMTC1
HGNC (Hugo) CTHRC1
LocusID (NCBI) 115908
Location 8q22.3
Location_base_pair Starts at 104384661 and ends at 104395232 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description CTHRC1 spans 4 exons and is a 1.2 kb transcript.

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.
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 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.
Localisation CTHRC1 has a signal peptide that targets it to the ER-Golgi 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.
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 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.
Homology 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.

Implicated in

Entity Breast cancer
Disease Lobular carcinoma and invasive ductal carcinoma
Prognosis Undetermined. Suggested that CTHRC1 expression in these tumors is associated with cancer tissue invasion and metastasis.
  
Entity 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.
  

External links

Nomenclature
HGNC (Hugo)CTHRC1   18831
Cards
AtlasCTHRC1ID40193ch8q22
Entrez_Gene (NCBI)CTHRC1  115908  collagen triple helix repeat containing 1
GeneCards (Weizmann)CTHRC1
Ensembl (Hinxton)ENSG00000164932 [Gene_View]  chr8:104384661-104395232 [Contig_View]  CTHRC1 [Vega]
ICGC DataPortalENSG00000164932
cBioPortalCTHRC1
AceView (NCBI)CTHRC1
Genatlas (Paris)CTHRC1
WikiGenes115908
SOURCE (Princeton)NM_001256099 NM_138455
Genomic and cartography
GoldenPath (UCSC)CTHRC1  -  8q22.3   chr8:104384661-104395232 +  8q22.3   [Description]    (hg19-Feb_2009)
EnsemblCTHRC1 - 8q22.3 [CytoView]
Mapping of homologs : NCBICTHRC1 [Mapview]
OMIM610635   614266   
Gene and transcription
Genbank (Entrez)AF395488 AI743774 AK130063 AK300273 AY136825
RefSeq transcript (Entrez)NM_001256099 NM_138455
RefSeq genomic (Entrez)AC_000140 NC_000008 NC_018919 NG_031985 NT_008046 NW_001839136 NW_004929340
Consensus coding sequences : CCDS (NCBI)CTHRC1
Cluster EST : UnigeneHs.405614 [ NCBI ]
CGAP (NCI)Hs.405614
Alternative Splicing : Fast-db (Paris)GSHG0029188
Alternative Splicing GalleryENSG00000164932
Gene ExpressionCTHRC1 [ NCBI-GEO ]     CTHRC1 [ SEEK ]   CTHRC1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96CG8 (Uniprot)
NextProtQ96CG8  [Medical]
With graphics : InterProQ96CG8
Splice isoforms : SwissVarQ96CG8 (Swissvar)
Domains : Interpro (EBI)Collagen [organisation]  
Related proteins : CluSTrQ96CG8
Domain families : Pfam (Sanger)Collagen (PF01391)   
Domain families : Pfam (NCBI)pfam01391   
DMDM Disease mutations115908
Blocks (Seattle)Q96CG8
Human Protein AtlasENSG00000164932 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ96CG8
HPRD16772
IPIIPI00060423   IPI00336091   IPI00909154   IPI00983832   
Protein Interaction databases
DIP (DOE-UCLA)Q96CG8
IntAct (EBI)Q96CG8
FunCoupENSG00000164932
BioGRIDCTHRC1
InParanoidQ96CG8
Interologous Interaction database Q96CG8
IntegromeDBCTHRC1
STRING (EMBL)CTHRC1
Ontologies - Pathways
Ontology : AmiGOfrizzled binding  proteinaceous extracellular matrix  collagen trimer  extracellular space  cytoplasm  cell migration  Wnt-protein binding  positive regulation of protein binding  positive regulation of osteoblast proliferation  ossification involved in bone remodeling  positive regulation of osteoblast differentiation  Wnt signaling pathway, planar cell polarity pathway  inner ear receptor stereocilium organization  negative regulation of canonical Wnt signaling pathway  cochlea morphogenesis  establishment of planar polarity involved in neural tube closure  
Ontology : EGO-EBIfrizzled binding  proteinaceous extracellular matrix  collagen trimer  extracellular space  cytoplasm  cell migration  Wnt-protein binding  positive regulation of protein binding  positive regulation of osteoblast proliferation  ossification involved in bone remodeling  positive regulation of osteoblast differentiation  Wnt signaling pathway, planar cell polarity pathway  inner ear receptor stereocilium organization  negative regulation of canonical Wnt signaling pathway  cochlea morphogenesis  establishment of planar polarity involved in neural tube closure  
Protein Interaction DatabaseCTHRC1
Wikipedia pathwaysCTHRC1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CTHRC1
snp3D : Map Gene to Disease115908
SNP (GeneSNP Utah)CTHRC1
SNP : HGBaseCTHRC1
Genetic variants : HAPMAPCTHRC1
Exome VariantCTHRC1
1000_GenomesCTHRC1 
ICGC programENSG00000164932 
Somatic Mutations in Cancer : COSMICCTHRC1 
CONAN: Copy Number AnalysisCTHRC1 
Mutations and Diseases : HGMDCTHRC1
Mutations and Diseases : intOGenCTHRC1
Genomic VariantsCTHRC1  CTHRC1 [DGVbeta]
dbVarCTHRC1
ClinVarCTHRC1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM610635    614266   
MedgenCTHRC1
GENETestsCTHRC1
Disease Genetic AssociationCTHRC1
Huge Navigator CTHRC1 [HugePedia]  CTHRC1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCTHRC1
Homology/Alignments : Family Browser (UCSC)CTHRC1
Phylogenetic Trees/Animal Genes : TreeFamCTHRC1
Chemical/Protein Interactions : CTD115908
Chemical/Pharm GKB GenePA38701
Clinical trialCTHRC1
Cancer Resource (Charite)ENSG00000164932
Other databases
Probes
Litterature
PubMed16 Pubmed reference(s) in Entrez
CoreMineCTHRC1
iHOPCTHRC1
OncoSearchCTHRC1

Bibliography

Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration.
Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L, Friesel RE, Lindner V.
Circ Res. 2005 Feb 4;96(2):261-8.
PMID 15618538
 
Expression analysis of the novel gene collagen triple helix repeat containing-1 (Cthrc1).
Durmus T, LeClair RJ, Park KS, Terzic A, Yoon JK, Lindner V.
Gene Expr Patterns. 2006 Oct;6(8):935-40.
PMID 16678498
 
Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers.
Tang L, Dai DL, Su M, Martinka M, Li G, Zhou Y.
Clin Cancer Res. 2006 Jun 15;12(12):3716-22.
PMID 16778098
 
The role of collagen triple helix repeat containing 1 in injured arteries, collagen expression, and transforming growth factor beta signaling.
LeClair R, Lindner V.
Trends Cardiovasc Med. 2007 Aug;17(6):202-5.
PMID 17662915
 
Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation.
LeClair RJ, Durmus T, Wang Q, Pyagay P, Terzic A, Lindner V.
Circ Res. 2007 Mar 30;100(6):826-33.
PMID 17322174
 
Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis.
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.
BMC Cancer. 2007 Mar 27;7:55.
PMID 17389037
 
[Construction of a subtracted cDNA library of chronic intermittent hypoxia rabbit liver by suppression subtractive hybridization].
Wu YT, Liu RH, Yang Y, Luo YQ, Rong Y.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Dec;32(6):1013-9.
PMID 18182719
 
Differential gene expression profiling in HELLP syndrome placentas.
Kang BY, Tsoi S, Zhu S, Su S, Kay HH.
Reprod Sci. 2008 Apr;15(3):285-94.
PMID 18421023
 
Leading Wnt down a PCP path: Cthrc1 acts as a coreceptor in the Wnt-PCP pathway.
Kelley MW.
Dev Cell. 2008 Jul;15(1):7-8.
PMID 18606135
 
Cthrc1 is a positive regulator of osteoblastic bone formation.
Kimura H, Kwan KM, Zhang Z, Deng JM, Darnay BG, Behringer RR, Nakamura T, de Crombrugghe B, Akiyama H.
PLoS ONE. 2008 Sep 9;3(9):e3174.
PMID 18779865
 
Intracellular localization of Cthrc1 characterizes differentiated smooth muscle.
Leclair RJ, Wang Q, Benson MA, Prudovsky I, Lindner V.
Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1332-8.
PMID 18467647
 
Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex.
Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S, Tarui H, Sasaki H.
Dev Cell. 2008 Jul;15(1):23-36.
PMID 18606138
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written11-2008Renee J LeClair, Tahir Durmus, Volkhard Lindner
Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA

Citation

This paper should be referenced as such :
LeClair, R ; Durmus, T ; Lindner, V
CTHRC1 (Collagen Triple Helix Repeat Containing 1)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):719-720.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CTHRC1ID40193ch8q22.html

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indexed on : Sat Oct 4 12:52:50 CEST 2014

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