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=== Cancer ===
=== Cancer ===


A [[frameshift mutation]] of TCF7L2 is implicated in [[colorectal cancer]].<ref name="pmid18398040">{{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 }}</ref><ref name="pmid18478343">{{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 }}</ref> Variants of the gene are most likely involved in many other cancer types.<ref name="pmid18621708">{{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 }}</ref>
TCF7L2 plays a role in [[colorectal cancer]].<ref name=":6">{{Cite journal|last=Torres|first=Sofía|last2=García-Palmero|first2=Irene|last3=Marín-Vicente|first3=Consuelo|last4=Bartolomé|first4=Rubén A.|last5=Calviño|first5=Eva|last6=Fernández-Aceñero|first6=María Jesús|last7=Casal|first7=J. Ignacio|date=2017-11-21|title=Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/29131639|journal=Journal of Proteome Research|doi=10.1021/acs.jproteome.7b00548|issn=1535-3907|pmid=29131639}}</ref> A [[frameshift mutation]] of TCF7L2 provided evidence that TCF7L2 is implicated in [[colorectal cancer]].<ref name="pmid18398040">{{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 }}</ref><ref name="pmid18478343">{{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 }}</ref> The silencing of TCF7L2 in KM12 colorectal cancer cells provided evidence that TCF7L2 played a role in [[Cell proliferation|proliferation]] and [[metastasis]] of cancer cells in [[colorectal cancer]].<ref name=":6" />

Variants of the gene are most likely involved in many other cancer types.<ref name="pmid18621708">{{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 }}</ref> TCF7L2 is indirectly involved in [[prostate cancer]] through its role in activating the [[PI3K/AKT/mTOR pathway|PI3K/Akt pathway]], a pathway involved in prostate cancer.<ref name=":12">{{Cite journal|last=Sun|first=Ping|last2=Xiong|first2=Hui|last3=Kim|first3=Tae Hoon|last4=Ren|first4=Bing|last5=Zhang|first5=Zhuohua|date=2006-02-01|title=Positive Inter-Regulation between β-Catenin/T Cell Factor-4 Signaling and Endothelin-1 Signaling Potentiates Proliferation and Survival of Prostate Cancer Cells|url=http://molpharm.aspetjournals.org/content/69/2/520|journal=Molecular Pharmacology|language=en|volume=69|issue=2|pages=520–531|doi=10.1124/mol.105.019620|issn=0026-895X|pmid=16291872}}</ref>

=== Schizophrenia ===
[[Single-nucleotide polymorphism|Single nucleotide polymorphisms (SNPs)]] in TCF7L2 gene have shown an increase in susceptibility to [[schizophrenia]] in Arab, European and Chinese Han populations.<ref name=":9">{{Cite journal|last=Liu|first=Lijun|last2=Li|first2=Jingjie|last3=Yan|first3=Mengdan|last4=Li|first4=Jing|last5=Chen|first5=Junyu|last6=Zhang|first6=Yi|last7=Zhu|first7=Xikai|last8=Wang|first8=Li|last9=Kang|first9=Longli|date=2017-02-22|title=TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438676/|journal=Oncotarget|volume=8|issue=17|pages=28614–28620|doi=10.18632/oncotarget.15603|issn=1949-2553|pmc=PMC5438676|pmid=28404897}}</ref> In the Chinese Han population, SNP rs12573128 in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. It is important to note the markers associated with those diseases to use them as pre-diagnostic markers.<ref name=":9" />

=== Multiple Sclerosis ===
TCF7L2 is downstream of the [[Wnt signaling pathway|WNT]]/[[Beta-catenin|β-catenin]] pathways. The activation of the [[Wnt signaling pathway|WNT]]/[[Beta-catenin|β-catenin]] pathway has been associated [[demyelination]] in [[multiple sclerosis]]. TCF7L2 is unregulated during early r[[Remyelination|emyelination]], leading scientists to believe that it is involved in [[remyelination]]. TCF7L2 could act in dependence or independent of the [[Wnt signaling pathway|WNT]]/[[Beta-catenin|β-catenin]] pathways.<ref name=":7">{{Cite journal|last=Vallée|first=Alexandre|last2=Vallée|first2=Jean-Noël|last3=Guillevin|first3=Rémy|last4=Lecarpentier|first4=Yves|date=2017-09-13|title=Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/28905149|journal=Cellular and Molecular Neurobiology|doi=10.1007/s10571-017-0550-9|issn=1573-6830|pmid=28905149}}</ref>


== Model organisms ==
== Model organisms ==

Revision as of 19:42, 30 November 2017

TCF7L2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTCF7L2, TCF-4, TCF4, transcription factor 7 like 2
External IDsOMIM: 602228 MGI: 1202879 HomoloGene: 7564 GeneCards: TCF7L2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 10: 112.95 – 113.17 MbChr 19: 55.73 – 55.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.[5][6]The TCF7L2 gene is located on chromosome 10q25.2-q25.3, contains 19 exons, and has an autosomal dominant inheritance type.[7][8] The single nucleotide polymorphism (SNP) within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker[9] associated with Type 2 diabetes mellitus (T2DM) risk. SNPs in this gene are linked to higher risk to develop type 2 diabetes,[10] as well as gestational diabetes.[11]

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown).[12]

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,[13] which in turn results in the activation of Wnt target genes, specifically repressing proglucagon synthesis in enteroendocrine cells.[10][14]

Clinical significance

Association with Type 2 Diabetes

Several 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 [15] This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene [16]. 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 [17] [18]

Cancer

TCF7L2 plays a role in colorectal cancer.[19] 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.[19]

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]

Schizophrenia

Single 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 in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. It is important to note the markers associated with those diseases to use them as pre-diagnostic markers.[24]

Multiple Sclerosis

TCF7L2 is downstream of the WNT/β-catenin pathways. The activation of the WNT/β-catenin pathway has been associated demyelination in multiple sclerosis. TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination. TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.[25]

Model organisms

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.[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]

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000148737Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024985Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: TCF7L2".
  6. ^ Castrop J, van Norren K, Clevers H (February 1992). "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Research. 20 (3): 611. doi:10.1093/nar/20.3.611. PMC 310434. PMID 1741298.
  7. ^ "TCF7L2 transcription factor 7 like 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-30.
  8. ^ "OMIM Entry-*602228-TRANSCRIPTION FACTOR 7-LIKE 2;TCF7L2". omim.org. Retrieved 2017-11-30.
  9. ^ Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC (October 2012). "Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk". Physiological Genomics. 44 (19): 903–14. doi:10.1152/physiolgenomics.00030.2012. PMID 22872755.
  10. ^ a b Jin T, Liu L (November 2008). "The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus". Molecular Endocrinology. 22 (11): 2383–92. doi:10.1210/me.2008-0135. PMID 18599616.
  11. ^ 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". Human Reproduction Update. 19 (4): 376–90. doi:10.1093/humupd/dmt013. PMC 3682671. PMID 23690305.
  12. ^ 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". Molecular Cell. 24 (2): 293–300. doi:10.1016/j.molcel.2006.09.001. PMID 17052462.
  13. ^ Lee JM, Dedhar S, Kalluri R, Thompson EW (March 2006). "The epithelial-mesenchymal transition: new insights in signaling, development, and disease". The Journal of Cell Biology. 172 (7): 973–81. doi:10.1083/jcb.200601018. PMC 2063755. PMID 16567498.
  14. ^ Online Mendelian Inheritance in Man (OMIM): 602228
  15. ^ Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O'Connell P, Stern MP (April 1999). "Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans". American Journal of Human Genetics. 64 (4): 1127–40. PMC 1377837. PMID 10090898.
  16. ^ 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 (March 2006). "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes". Nature Genetics. 38 (3): 320–3. doi:10.1038/ng1732. PMID 16415884.
  17. ^ Nobrega MA (March 2013). "TCF7L2 and glucose metabolism: time to look beyond the pancreas". Diabetes. 62 (3): 706–8. doi:10.2337/db12-1418. PMC 3581232. PMID 23431017.
  18. ^ Jin T (June 2016). "Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis". Endocrine Reviews. 37 (3): 254–77. doi:10.1210/er.2015-1146. PMID 27159876.
  19. ^ a b Torres, Sofía; García-Palmero, Irene; Marín-Vicente, Consuelo; Bartolomé, Rubén A.; Calviño, Eva; Fernández-Aceñero, María Jesús; Casal, J. Ignacio (2017-11-21). "Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer". Journal of Proteome Research. doi:10.1021/acs.jproteome.7b00548. ISSN 1535-3907. PMID 29131639.
  20. ^ Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD (April 2008). "Transcription factor 7-like 2 polymorphism and colon cancer". Cancer Epidemiology, Biomarkers & Prevention. 17 (4): 978–82. doi:10.1158/1055-9965.EPI-07-2687. PMC 2587179. PMID 18398040.
  21. ^ Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ (November 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 2719293. PMID 18478343.
  22. ^ Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L (July 2008). "A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer". Proceedings of the National Academy of Sciences of the United States of America. 105 (28): 9697–702. Bibcode:2008PNAS..105.9697T. doi:10.1073/pnas.0804709105. PMC 2453074. PMID 18621708.
  23. ^ Sun, Ping; Xiong, Hui; Kim, Tae Hoon; Ren, Bing; Zhang, Zhuohua (2006-02-01). "Positive Inter-Regulation between β-Catenin/T Cell Factor-4 Signaling and Endothelin-1 Signaling Potentiates Proliferation and Survival of Prostate Cancer Cells". Molecular Pharmacology. 69 (2): 520–531. doi:10.1124/mol.105.019620. ISSN 0026-895X. PMID 16291872.
  24. ^ a b Liu, Lijun; Li, Jingjie; Yan, Mengdan; Li, Jing; Chen, Junyu; Zhang, Yi; Zhu, Xikai; Wang, Li; Kang, Longli (2017-02-22). "TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population". Oncotarget. 8 (17): 28614–28620. doi:10.18632/oncotarget.15603. ISSN 1949-2553. PMC 5438676. PMID 28404897.{{cite journal}}: CS1 maint: PMC format (link)
  25. ^ Vallée, Alexandre; Vallée, Jean-Noël; Guillevin, Rémy; Lecarpentier, Yves (2017-09-13). "Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis". Cellular and Molecular Neurobiology. doi:10.1007/s10571-017-0550-9. ISSN 1573-6830. PMID 28905149.
  26. ^ 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.
  27. ^ "International Mouse Phenotyping Consortium".
  28. ^ 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 (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  29. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  30. ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  31. ^ 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 (July 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 3717207. PMID 23870131.
  32. ^ "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

External links