TCF7L2

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TCF7L2
Protein TCF7L2 PDB 1jdh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TCF7L2, TCF-4, TCF4, transcription factor 7 like 2
External IDs OMIM: 602228 MGI: 1202879 HomoloGene: 7564 GeneCards: TCF7L2
Genetically Related Diseases
type 2 diabetes mellitus, bipolar disorder, breast cancer, coronary artery disease, disease of metabolism, colorectal cancer[1]
RNA expression pattern
PBB GE TCF7L2 212762 s at fs.png

PBB GE TCF7L2 212759 s at fs.png

PBB GE TCF7L2 212761 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr 10: 112.95 – 113.17 Mb Chr 19: 55.74 – 55.93 Mb
PubMed search [2] [3]
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.[4][5] The single nucleotide polymorphism (SNP) within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker[6] associated with Type 2 diabetes mellitus (T2DM) risk. SNPs in this gene are linked to higher risk to develop type 2 diabetes,[7] as well as gestational diabetes.[8]

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown).[9]

Function[edit]

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,[10] which in turn results in the activation of Wnt target genes, specifically repressing proglucagon synthesis in enteroendocrine cells.[7][11]

Clinical significance[edit]

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.[7]

A frameshift mutation of TCF7L2 is implicated in colorectal cancer.[12][13] Variants of the gene are most likely involved in many other cancer types.[14]

Model organisms[edit]

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[15] Male and female animals underwent a standardized phenotypic screen[16] to determine the effects of deletion.[17][18][19][20] Additional screens performed: - In-depth immunological phenotyping[21]

Nomenclature[edit]

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[edit]

References[edit]

  1. ^ "Diseases that are genetically associated with TCF7L2 view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ "Entrez Gene: TCF7L2". 
  5. ^ 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 310434Freely accessible. PMID 1741298. 
  6. ^ Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC (2012). "Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk". Physiol. Genomics. 44 (19): 903–14. doi:10.1152/physiolgenomics.00030.2012. PMID 22872755. 
  7. ^ a b c Jin T, Liu L (2008). "The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus". Mol. Endocrinol. 22 (11): 2383–92. doi:10.1210/me.2008-0135. PMID 18599616. 
  8. ^ Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M (2013). "Genetic variants and the risk of gestational diabetes mellitus: a systematic review". Hum. Reprod. Update. 19 (4): 376–90. doi:10.1093/humupd/dmt013. PMID 23690305. 
  9. ^ PDB: 2GL7​; Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W (October 2006). "Crystal structure of a beta-catenin/BCL9/Tcf4 complex". Mol. Cell. 24 (2): 293–300. doi:10.1016/j.molcel.2006.09.001. PMID 17052462. 
  10. ^ Lee JM, Dedhar S, Kalluri R, Thompson EW (2006). "The epithelial-mesenchymal transition: new insights in signaling, development, and disease". J. Cell Biol. 172 (7): 973–81. doi:10.1083/jcb.200601018. PMC 2063755Freely accessible. PMID 16567498. 
  11. ^ Online Mendelian Inheritance in Man (OMIM) 602228
  12. ^ Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD (2008). "Transcription factor 7-like 2 polymorphism and colon cancer". Cancer Epidemiol. Biomarkers Prev. 17 (4): 978–82. doi:10.1158/1055-9965.EPI-07-2687. PMC 2587179Freely accessible. PMID 18398040. 
  13. ^ Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ (2008). "Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk". Cancer Causes Control. 19 (9): 975–80. doi:10.1007/s10552-008-9164-3. PMC 2719293Freely accessible. PMID 18478343. 
  14. ^ Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L (2008). "A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer". Proc. Natl. Acad. Sci. U.S.A. 105 (28): 9697–702. Bibcode:2008PNAS..105.9697T. doi:10.1073/pnas.0804709105. PMC 2453074Freely accessible. PMID 18621708. 
  15. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  16. ^ a b "International Mouse Phenotyping Consortium". 
  17. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410Freely accessible. PMID 21677750. 
  18. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  19. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  20. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207Freely accessible. PMID 23870131. 
  21. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 

Further reading[edit]

External links[edit]

  • 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