词条 | TCF7L2 |
释义 |
FunctionTCF7L2 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 TCF family that can form a bipartite transcription factor (β-catenin/TCF) alongside β-catenin.[7] Bipartite transcription factors can have large effects on the Wnt signalling pathway.[7] Stimulation of the Wnt signaling 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. The activation of the Wnt target genes specifically represses proglucagon synthesis in enteroendocrine cells.[7][4] The repression of TCF7L2 using HMG-box repressor (HBP1) inhibits Wnt signalling.[7] Therefore, TCF7L2 is an effector in the Wnt signalling pathway. TCF7L2's role in glucose metabolism is expressed in many tissues such as gut, brain, liver, and skeletal muscle. However, TCF7L2 does not directly regulate glucose metabolism in β-cells, but regulates glucose metabolism in pancreatic and liver tissues.[11] The TCF7L2 gene encoding the TCF7L2 transcription factor, exhibits multiple functions through its polymorphisms and thus, is known as a pleiotropic gene. Type 2 diabetes T2DM susceptibility is exhibited in carriers of TCF7L2 rs7903146C>T[12][5] and rs290481T>C[5] polymorphisms.[12][5] TCF7L2 rs290481T>C polymorphism, however, has shown no significant correlation to the susceptibility to gestational diabetes mellitus (GDM) in a Chinese Han population, whereas the T alleles of rs7903146[5] and rs1799884[13] increase susceptibility to GDM in the Chinese Han population.[5][13] The difference in effects of the different polymorphisms of the gene indicate that the gene is indeed pleiotropic. StructureThe TCF7L2 gene, encoding the TCF7L2 protein, is located on chromosome 10q25.2-q25.3. The gene contains 19 exons and has autosomal dominant inheritance.[3][4] Of the 19 exons, 5 are alternative.[4] The TCF7L2 gene contains 619 amino acids and its molecular mass is 67919 Da.[14] TCF7L2's secondary structure is a helix-turn-helix structure.[15] Tissue DistributionTCF7L2 does not primarily operate in the β-cells in the pancreas.[16] It is also expressed in brain, liver, intestine, and fat cells.[16] Clinical significanceType 2 DiabetesSeveral single nucleotide polymorphisms within the TCF7L2 gene have been associated with type 2 diabetes. Studies conducted by Ravindranath Duggirala and Michael Stern at The University of Texas Health Science Center at San Antonio were the first to identify strong linkage for type 2 diabetes at a region on Chromosome 10 in Mexican Americans [17] This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene.[18] The molecular and physiological mechanisms underlying the association of TCF7L2 with type 2 diabetes are under active investigation, but it is likely that TCF7L2 has important biological roles in multiple metabolic tissues, including the pancreas, liver and adipose tissue.[16][19] TCF7L2 polymorphisms can increase susceptibility to type 2 diabetes by decreasing the production of glucagon-like peptide-1 (GLP-1).[7] Gestational Diabetes (GDM)TCF7L2 modulates pancreatic islet β-cell function strongly implicating its significant association with GDM risk.[13] T alleles of rs7903146[5] and rs1799884[13] TCF7L2 polymorphisms increase susceptibility to GDM in the Chinese Han population.[5][13] CancerTCF7L2 plays a role in colorectal cancer.[8] A frameshift mutation of TCF7L2 provided evidence that TCF7L2 is implicated in colorectal cancer.[20][21] The silencing of TCF7L2 in KM12 colorectal cancer cells provided evidence that TCF7L2 played a role in proliferation and metastasis of cancer cells in colorectal cancer.[8] Variants of the gene are most likely involved in many other cancer types.[22] TCF7L2 is indirectly involved in prostate cancer through its role in activating the PI3K/Akt pathway, a pathway involved in prostate cancer.[23] SchizophreniaSingle nucleotide polymorphisms (SNPs) in TCF7L2 gene have shown an increase in susceptibility to schizophrenia in Arab, European and Chinese Han populations.[24] In the Chinese Han population, SNP rs12573128[24] in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. This marker is used as a pre-diagnostic marker for schizophrenia.[24] Multiple SclerosisTCF7L2 is downstream of the WNT/β-catenin pathways. The activation of the WNT/β-catenin pathways have been associated demyelination in multiple sclerosis.[12] TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination.[12] TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.[25] Model organismsModel 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.[26] Male and female animals underwent a standardized phenotypic screen[27] to determine the effects of deletion.[28][29][30][31] Additional screens performed: - In-depth immunological phenotyping[32]Variations of the protein encoding gene are found in rats, zebra fish, drosophila, and budding yeast.[33] Therefore, all of those organisms can be used as model organisms in the study of TCF7L2 function. {{clear|left}}
NomenclatureTCF7L2 is the symbol officially approved by the HUGO Gene Nomenclature Committee for the transcription factor 4 gene (TCF4). See also
References1. ^{{cite web | title = Entrez Gene: TCF7L2 | url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6934 }} 2. ^{{cite journal | vauthors = Castrop J, van Norren K, Clevers H | title = A gene family of HMG-box transcription factors with homology to TCF-1 | journal = Nucleic Acids Research | volume = 20 | issue = 3 | pages = 611 | date = February 1992 | pmid = 1741298 | pmc = 310434 | doi = 10.1093/nar/20.3.611 }} 3. ^1 {{cite web|url=https://www.ncbi.nlm.nih.gov/gene/6934|title=TCF7L2 transcription factor 7 like 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-11-30}} 4. ^1 2 3 {{OMIM|602228|TRANSCRIPTION FACTOR 7-LIKE 2;TCF7L2 }}{ 5. ^1 2 3 4 5 6 7 {{cite journal | vauthors = Zhu L, Xie Z, Lu J, Hao Q, Kang M, Chen S, Tang W, Ding H, Chen Y, Liu C, Wu H | title = TCF7L2 rs290481 T>C polymorphism is associated with an increased risk of type 2 diabetes mellitus and fasting plasma glucose level | journal = Oncotarget | volume = 8 | issue = 44 | pages = 77000–77008 | date = September 2017 | pmid = 29100364 | pmc = 5652758 | doi = 10.18632/oncotarget.20300 }} 6. ^{{cite journal | vauthors = Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC | title = Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk | journal = Physiological Genomics | volume = 44 | issue = 19 | pages = 903–14 | date = October 2012 | pmid = 22872755 | doi = 10.1152/physiolgenomics.00030.2012 }} 7. ^1 2 3 4 5 6 {{cite journal | vauthors = Jin T, Liu L | title = The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus | journal = Molecular Endocrinology | volume = 22 | issue = 11 | pages = 2383–92 | date = November 2008 | pmid = 18599616 | doi = 10.1210/me.2008-0135 }} 8. ^1 2 {{cite journal | vauthors = Torres S, García-Palmero I, Marín-Vicente C, Bartolomé RA, Calviño E, Fernández-Aceñero MJ, Casal JI | title = Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer | journal = Journal of Proteome Research | date = November 2017 | pmid = 29131639 | doi = 10.1021/acs.jproteome.7b00548 | volume=17 | issue = 1 | pages=252–264}} 9. ^{{PDB|2GL7}}; {{cite journal | vauthors = Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W | title = Crystal structure of a beta-catenin/BCL9/Tcf4 complex | journal = Molecular Cell | volume = 24 | issue = 2 | pages = 293–300 | date = October 2006 | pmid = 17052462 | doi = 10.1016/j.molcel.2006.09.001 }} 10. ^{{cite journal | vauthors = Lee JM, Dedhar S, Kalluri R, Thompson EW | title = The epithelial-mesenchymal transition: new insights in signaling, development, and disease | journal = The Journal of Cell Biology | volume = 172 | issue = 7 | pages = 973–81 | date = March 2006 | pmid = 16567498 | pmc = 2063755 | doi = 10.1083/jcb.200601018 }} 11. ^{{cite journal | vauthors = Facchinello N, Tarifeño-Saldivia E, Grisan E, Schiavone M, Peron M, Mongera A, Ek O, Schmitner N, Meyer D, Peers B, Tiso N, Argenton F | title = Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 9605 | date = August 2017 | pmid = 28851992 | pmc = 5575064 | doi = 10.1038/s41598-017-09867-x | bibcode = 2017NatSR...7.9605F }} 12. ^1 {{cite journal | vauthors = Chen Y, Zhao Y, Li YB, Wang YJ, Zhang GZ | title = Detection of SNPs of T2DM susceptibility genes by a ligase detection reaction-fluorescent nanosphere technique | journal = Analytical Biochemistry | volume = 540–541 | issue = Supplement C | pages = 38–44 | date = January 2018 | pmid = 29128291 | doi = 10.1016/j.ab.2017.11.003 }} 13. ^1 2 3 4 5 {{cite journal | vauthors = Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M | title = Genetic variants and the risk of gestational diabetes mellitus: a systematic review | journal = Human Reproduction Update | volume = 19 | issue = 4 | pages = 376–90 | date = 2013-05-19 | pmid = 23690305 | pmc = 3682671 | doi = 10.1093/humupd/dmt013 }} 14. ^{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF7L2|title=TCF7L2 Gene - GeneCards {{!}} TF7L2 Protein {{!}} TF7L2 Antibody|last=Database|first=GeneCards Human Gene|website=www.genecards.org|access-date=2017-11-30}} 15. ^{{Cite web|url=https://www.uniprot.org/uniprot/Q9NQB0|title=TCF7L2 - Transcription factor 7-like 2 - Homo sapiens (Human) - TCF7L2 gene & protein|website=www.uniprot.org|language=en|access-date=2017-11-30}} 16. ^1 2 {{cite journal | vauthors = Nobrega MA | title = TCF7L2 and glucose metabolism: time to look beyond the pancreas | journal = Diabetes | volume = 62 | issue = 3 | pages = 706–8 | date = March 2013 | pmid = 23431017 | pmc = 3581232 | doi = 10.2337/db12-1418 }} 17. ^{{cite journal | vauthors = Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O'Connell P, Stern MP | title = Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans | journal = American Journal of Human Genetics | volume = 64 | issue = 4 | pages = 1127–40 | date = April 1999 | pmid = 10090898 | pmc = 1377837 | doi=10.1086/302316}} 18. ^{{cite journal | vauthors = Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K | title = Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes | journal = Nature Genetics | volume = 38 | issue = 3 | pages = 320–3 | date = March 2006 | pmid = 16415884 | pmc = | doi = 10.1038/ng1732 }} 19. ^{{cite journal | vauthors = Jin T | title = Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis | journal = Endocrine Reviews | volume = 37 | issue = 3 | pages = 254–77 | date = June 2016 | pmid = 27159876 | pmc = | doi = 10.1210/er.2015-1146 }} 20. ^{{cite journal | vauthors = Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD | title = Transcription factor 7-like 2 polymorphism and colon cancer | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 17 | issue = 4 | pages = 978–82 | date = April 2008 | pmid = 18398040 | pmc = 2587179 | doi = 10.1158/1055-9965.EPI-07-2687 }} 21. ^{{cite journal | vauthors = Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ | title = Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk | journal = Cancer Causes & Control | volume = 19 | issue = 9 | pages = 975–80 | date = November 2008 | pmid = 18478343 | pmc = 2719293 | doi = 10.1007/s10552-008-9164-3 }} 22. ^{{cite journal | vauthors = Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L | title = A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 28 | pages = 9697–702 | date = July 2008 | pmid = 18621708 | pmc = 2453074 | doi = 10.1073/pnas.0804709105 | bibcode = 2008PNAS..105.9697T }} 23. ^{{cite journal | vauthors = Sun P, Xiong H, Kim TH, Ren B, Zhang Z | title = Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells | journal = Molecular Pharmacology | volume = 69 | issue = 2 | pages = 520–31 | date = February 2006 | pmid = 16291872 | doi = 10.1124/mol.105.019620 }} 24. ^1 2 3 {{cite journal | vauthors = Liu L, Li J, Yan M, Li J, Chen J, Zhang Y, Zhu X, Wang L, Kang L, Yuan D, Jin T | title = TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population | journal = Oncotarget | volume = 8 | issue = 17 | pages = 28614–28620 | date = April 2017 | pmid = 28404897 | pmc = 5438676 | doi = 10.18632/oncotarget.15603 }} 25. ^1 2 3 {{cite journal | vauthors = Vallée A, Vallée JN, Guillevin R, Lecarpentier Y | title = Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis | journal = Cellular and Molecular Neurobiology | volume = 38 | issue = 4 | pages = 783–795 | date = September 2017 | pmid = 28905149 | doi = 10.1007/s10571-017-0550-9 }} 26. ^{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice | vauthors = Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }} 27. ^{{cite web |url=http://www.mousephenotype.org/data/search?q=Tcf7l2#fq=**&facet=gene |title=International Mouse Phenotyping Consortium}} 28. ^{{cite journal | vauthors = 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 | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }} 29. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }} 30. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }} 31. ^{{cite journal | vauthors = 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, 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 | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = July 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }} 32. ^{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Tcf7l2&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}} 33. ^{{Cite web|url=http://marrvel.org/search/gene/TCF7L2|title=MARRVEL: Search Result|website=marrvel.org|access-date=2017-11-30}} Further reading{{refbegin|33em}}
External links
3 : Transcription factors|Signal transduction|Gene expression |
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