TCF7L2

TCF7L2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2GL7, 1JDH, 1JPW
Identifiers
Aliases	TCF7L2, TCF-4, TCF4, transcription factor 7 like 2
External IDs	OMIM: 602228 MGI: 1202879 HomoloGene: 7564 GeneCards: TCF7L2
Gene location (Human) Chr. Chromosome 10 (human) Band 10q25.2-q25.3 Start 112,950,247 bp End 113,167,678 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19 D2|19 51.59 cM Start 55,730,252 bp End 55,922,086 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell pancreatic ductal cell hair follicle lactiferous duct tibia visceral pleura germinal epithelium parietal pleura jejunal mucosa saphenous vein Top expressed in medial dorsal nucleus medial geniculate nucleus habenula lateral geniculate nucleus inferior colliculus ascending aorta aortic valve internal carotid artery external carotid artery left colon More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sequence-specific DNA binding DNA binding beta-catenin binding gamma-catenin binding DNA-binding transcription factor activity transcription factor binding RNA polymerase II cis-regulatory region sequence-specific DNA binding protein binding armadillo repeat domain binding protein kinase binding DNA-binding transcription factor activity, RNA polymerase II-specific chromatin binding Cellular component beta-catenin-TCF7L2 complex PML body nucleoplasm protein-DNA complex nucleus transcription regulator complex Biological process positive regulation of heparan sulfate proteoglycan biosynthetic process positive regulation of protein kinase B signaling regulation of transcription, DNA-templated glucose homeostasis regulation of transcription by RNA polymerase II response to glucose Wnt signaling pathway regulation of smooth muscle cell proliferation negative regulation of DNA-binding transcription factor activity canonical Wnt signaling pathway involved in positive regulation of epithelial to mesenchymal transition transcription, DNA-templated positive regulation of protein export from nucleus maintenance of DNA repeat elements blood vessel development myoblast fate commitment canonical Wnt signaling pathway pancreas development positive regulation of protein binding regulation of hormone metabolic process cell population proliferation negative regulation of transcription, DNA-templated fat cell differentiation negative regulation of canonical Wnt signaling pathway beta-catenin-TCF complex assembly Wnt signaling pathway, calcium modulating pathway positive regulation of insulin secretion negative regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II negative regulation of type B pancreatic cell apoptotic process negative regulation of extrinsic apoptotic signaling pathway positive regulation of epithelial cell proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6934 21416 Ensembl ENSG00000148737 ENSMUSG00000024985 UniProt Q9NQB0 Q924A0 RefSeq (mRNA) NM_001146274 NM_001146283 NM_001146284 NM_001146285 NM_001146286 NM_001198525 NM_001198526 NM_001198527 NM_001198528 NM_001198529 NM_001198530 NM_001198531 NM_030756 NM_001349870 NM_001349871 NM_001363501 NM_001367943 NM_001142918 NM_001142919 NM_001142920 NM_001142921 NM_001142922 NM_001142923 NM_001142924 NM_009333 NM_001331135 NM_001331136 NM_001331137 NM_001331138 NM_001331139 NM_001331140 NM_001331141 NM_001331142 NM_001331143 NM_001331144 NM_001331145 NM_001331146 NM_001331147 NM_001331148 NM_001331149 NM_001331150 RefSeq (protein) NP_001139746 NP_001139755 NP_001139756 NP_001139757 NP_001139758 NP_001185454 NP_001185455 NP_001185456 NP_001185457 NP_001185458 NP_001185459 NP_001185460 NP_110383 NP_001336799 NP_001336800 NP_001350430 NP_001354872 NP_001139757.1 NP_001136390 NP_001136391 NP_001136392 NP_001136393 NP_001136394 NP_001136395 NP_001136396 NP_001318064 NP_001318065 NP_001318066 NP_001318067 NP_001318068 NP_001318069 NP_001318070 NP_001318071 NP_001318072 NP_001318073 NP_001318074 NP_001318075 NP_001318076 NP_001318077 NP_001318078 NP_001318079 NP_033359 Location (UCSC) Chr 10: 112.95 – 113.17 Mb Chr 19: 55.73 – 55.92 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Transcription factor 7-like 2 (T-cell specific, HMG-box) also known as TCF7L2 or TCF4 is a protein acting as a transcription factor. In humans this protein is encoded by the TCF7L2 gene. The single nucleotide polymorphism (SNP) within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker associated with Type 2 diabetes mellitus (T2DM) risk. SNPs in this gene are linked to higher risk to develop type 2 diabetes, as well as gestational diabetes.

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown).

Function

TCF7L2 is a transcription factor influencing the transcription of several genes thereby exerting a large variety of functions within the cell. It is a member of the Wnt signaling pathway. Stimulation of the pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2, which in turn results in the activation of Wnt target genes, specifically repressing proglucagon synthesis in enteroendocrine cells.

Clinical significance

TCF7L2 is implicated in a large variety of diseases. Several single nucleotide polymorphisms are associated with type 2 diabetes. In European populations it was found to be a major determinant of type 2 risk.

A frameshift mutation of TCF7L2 is implicated in colorectal cancer. Variants of the gene are most likely involved in many other cancer types.

Model organisms

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2^{tm1a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

Tcf7l2 knockout mouse phenotype

Characteristic	Phenotype
All data available at.
Insulin	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Abnormal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

Nomenclature

While TCF4 is sometimes misleadingly used as an alias symbol for TCF7L2, it is also the symbol officially approved by the HUGO Gene Nomenclature Committee for the transcription factor 4 gene.

See also

• TCF/LEF family

Further reading

• Segditsas S, Tomlinson I (2006). "Colorectal cancer and genetic alterations in the Wnt pathway". Oncogene. 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297.
• Florez JC (2007). "The new type 2 diabetes gene TCF7L2". Curr Opin Clin Nutr Metab Care. 10 (4): 391–6. doi:10.1097/MCO.0b013e3281e2c9be. PMID 17563454.
• Castrop J, van Norren K, Clevers H (1992). "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Res. 20 (3): 611. doi:10.1093/nar/20.3.611. PMC 310434. PMID 1741298.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H (1997). "Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma". Science. 275 (5307): 1784–7. doi:10.1126/science.275.5307.1784. PMID 9065401. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998). "Identification of c-MYC as a target of the APC pathway". Science. 281 (5382): 1509–12. Bibcode:1998Sci...281.1509H. doi:10.1126/science.281.5382.1509. PMID 9727977. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• Barker N, Huls G, Korinek V, Clevers H (1999). "Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium". Am. J. Pathol. 154 (1): 29–35. doi:10.1016/S0002-9440(10)65247-9. PMC 1853446. PMID 9916915.
• Omer CA, Miller PJ, Diehl RE, Kral AM (1999). "Identification of Tcf4 residues involved in high-affinity beta-catenin binding". Biochem. Biophys. Res. Commun. 256 (3): 584–90. doi:10.1006/bbrc.1999.0379. PMID 10080941.
• Giannini AL, Vivanco MM, Kypta RM (2000). "Analysis of beta-catenin aggregation and localization using GFP fusion proteins: nuclear import of alpha-catenin by the beta-catenin/Tcf complex". Exp. Cell Res. 255 (2): 207–20. doi:10.1006/excr.1999.4785. PMID 10694436.
• Duval A, Busson-Leconiat M, Berger R, Hamelin R (2000). "Assignment of the TCF-4 gene (TCF7L2) to human chromosome band 10q25.3". Cytogenet. Cell Genet. 88 (3–4): 264–5. doi:10.1159/000015534. PMID 10828605.
• Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R (2000). "The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines". Cancer Res. 60 (14): 3872–9. PMID 10919662. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• Brantjes H, Roose J, van De Wetering M, Clevers H (2001). "All Tcf HMG box transcription factors interact with Groucho-related co-repressors". Nucleic Acids Res. 29 (7): 1410–9. doi:10.1093/nar/29.7.1410. PMC 31284. PMID 11266540.
• Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B (2001). "Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion". J. Biol. Chem. 276 (42): 38563–9. doi:10.1074/jbc.M105376200. PMID 11504726. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)CS1 maint: unflagged free DOI (link)
• Miravet S, Piedra J, Miró F, Itarte E, García de Herreros A, Duñach M (2002). "The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin". J. Biol. Chem. 277 (3): 1884–91. doi:10.1074/jbc.M110248200. PMID 11711551. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)CS1 maint: unflagged free DOI (link)
• Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W (2001). "Tcf4 can specifically recognize beta-catenin using alternative conformations". Nat. Struct. Biol. 8 (12): 1048–52. doi:10.1038/nsb718. PMID 11713475. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• Poy F, Lepourcelet M, Shivdasani RA, Eck MJ (2001). "Structure of a human Tcf4-beta-catenin complex". Nat. Struct. Biol. 8 (12): 1053–7. doi:10.1038/nsb720. PMID 11713476.
• Thiele A, Wasner M, Müller C, Engeland K, Hauschildt S (2001). "Regulation and possible function of beta-catenin in human monocytes". J. Immunol. 167 (12): 6786–93. doi:10.4049/jimmunol.167.12.6786. PMID 11739494. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
• Marchenko GN, Marchenko ND, Leng J, Strongin AY (2002). "Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin". Biochem. J. 363 (Pt 2): 253–62. doi:10.1042/0264-6021:3630253. PMC 1222473. PMID 11931652.
• Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER (2002). "Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling". J. Biol. Chem. 277 (24): 21657–65. doi:10.1074/jbc.M200139200. PMID 11940574. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)CS1 maint: unflagged free DOI (link)

External links

• TCF7L2 here called TCF4 features on this Wnt pathway web site: Wnt signalling molecules TCFs
• Structure determination of TCF7L2: PDB entry 2GL7 and related publication on PubMed
• PubMed GeneRIFs (summaries of related scientific publications) - [1]
• Weizmann Institute GeneCard for TCF7L2