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Gene Review

TCF4  -  transcription factor 4

Homo sapiens

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A word of caution

This page is somewhat confusing, as it is headed with "transcription factor 4 (TCF4)" however many of the details below refer to T-cell factor 4 (TCF4, or TCF7L2). These are two entirely different genes.


Disease relevance of TCF4

  • Hemizygosity of TCF4 is one of the causes of Pitt-Hopkins   syndrome [1]. Multiple individuals are identified who have hemizygous deletions of all or a part of this gene. Penetrance is very high since no hemizygous individuals have been identified without this phenotype.
  • Hedgehog (Hh) signaling restricts the expression of Wnt targets to the base of the colonic crypt in vivo, and transfection of Ihh into colon cancer cells leads to a downregulation of both components of the nuclear TCF4-beta-catenin complex and abrogates endogenous Wnt signaling in vitro [2].
  • A colorectal carcinoma cell line, DLD-1, was engineered to suppress transactivation by the TCF4/beta-catenin complex in a dominant-negative manner under the strict control of the tetracycline regulatory system [3].
  • The full-length TCF4 cDNA clone was obtained from a HTLV-1 transformed human peripheral T cell MACHERMAKER cDNA library with NRE as the bait in yeast one-hybrid system [4].
  • Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter [5].
  • HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex [6].

Psychiatry related information on TCF4

  • Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder [7].
  • ITF2 was found to directly bind to negative acting Id HLH proteins and positive acting bHLH proteins such as scleraxis [8].
  • At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder [9].

High impact information on TCF4


Chemical compound and disease context of TCF4

  • Src-dependent activation of beta-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated beta-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its trans-activating ability in colorectal cancer cells [13].

Biological context of TCF4


Anatomical context of TCF4


Associations of TCF4 with chemical compounds

  • Furthermore, TCF4, which is one of the transcriptional factors in the Wnt signaling pathway and has a mononucleotide repeat sequence (a nine- adenine repeat, (A)9) in its C-terminal region, was mutated in 13 of the 33 samples [21].
  • Furthermore, the ectopic expression of beta-catenin-TCF4 in cells that constitutively express low levels of the transactivation complex produces a significant increase of GLCE transcript level and, at the same time, enhances the rate of D-glucuronic acid epimerization in HS [22].
  • In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50% [23].
  • These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3beta phosphorylation and the enhancement of TCF-4 transcriptional activity [24].
  • Ca(2+) strongly induced E-cadherin expression and inhibited the expression of the nuclear transcription factor, TCF4 [25].

Physical interactions of TCF4

  • The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo [6].
  • Binding studies in solution and in heterogeneous phase showed that TCF4 binds reversibly to beta-catenin with an affinity (KB) of 3(+/-1) 10(8) M(-1) [26].

Regulatory relationships of TCF4


Other interactions of TCF4


Analytical, diagnostic and therapeutic context of TCF4


  1. Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Rosenfeld, J.A., Leppig, K., Ballif, B.C., Thiese, H., Erdie-Lalena, C., Bawle, E., Sastry, S., Spence, J.E., Bandholz, A., Surti, U., Zonana, J., Keller, K., Meschino, W., Bejjani, B.A., Torchia, B.S., Shaffer, L.G. Genet. Med. (2009) [Pubmed]
  2. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. van den Brink, G.R., Bleuming, S.A., Hardwick, J.C., Schepman, B.L., Offerhaus, G.J., Keller, J.J., Nielsen, C., Gaffield, W., van Deventer, S.J., Roberts, D.J., Peppelenbosch, M.P. Nat. Genet. (2004) [Pubmed]
  3. Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Yamada, T., Takaoka, A.S., Naishiro, Y., Hayashi, R., Maruyama, K., Maesawa, C., Ochiai, A., Hirohashi, S. Cancer Res. (2000) [Pubmed]
  4. A negative regulatory element-dependent inhibitory role of ITF2B on IL-2 receptor alpha gene. Lu, Y., Sheng, D.Q., Mo, Z.C., Li, H.F., Wu, N.H., Shen, Y.F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  5. A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4. Amir, A.L., Barua, M., McKnight, N.C., Cheng, S., Yuan, X., Balk, S.P. J. Biol. Chem. (2003) [Pubmed]
  6. HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex. Persson, P., Jögi, A., Grynfeld, A., Påhlman, S., Axelson, H. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  7. Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder. Vincent, J.B., Petronis, A., Strong, E., Parikh, S.V., Meltzer, H.Y., Lieberman, J., Kennedy, J.L. Mol. Psychiatry (1999) [Pubmed]
  8. Role of the basic helix-loop-helix protein ITF2 in the hormonal regulation of Sertoli cell differentiation. Muir, T., Sadler-Riggleman, I., Stevens, J.D., Skinner, M.K. Mol. Reprod. Dev. (2006) [Pubmed]
  9. The unstable trinucleotide repeat story of major psychosis. Vincent, J.B., Paterson, A.D., Strong, E., Petronis, A., Kennedy, J.L. Am. J. Med. Genet. (2000) [Pubmed]
  10. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Grant, S.F., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Manolescu, A., Sainz, J., Helgason, A., Stefansson, H., Emilsson, V., Helgadottir, A., Styrkarsdottir, U., Magnusson, K.P., Walters, G.B., Palsdottir, E., Jonsdottir, T., Gudmundsdottir, T., Gylfason, A., Saemundsdottir, J., Wilensky, R.L., Reilly, M.P., Rader, D.J., Bagger, Y., Christiansen, C., Gudnason, V., Sigurdsson, G., Thorsteinsdottir, U., Gulcher, J.R., Kong, A., Stefansson, K. Nat. Genet. (2006) [Pubmed]
  11. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A.P., Tjon-Pon-Fong, M., Moerer, P., van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., Clevers, H. Cell (2002) [Pubmed]
  12. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Henthorn, P., Kiledjian, M., Kadesch, T. Science (1990) [Pubmed]
  13. SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Coluccia, A.M., Benati, D., Dekhil, H., De Filippo, A., Lan, C., Gambacorti-Passerini, C. Cancer Res. (2006) [Pubmed]
  14. A yeast model system for functional analysis of beta-catenin signaling. Lee, M.S., D'Amour, K.A., Papkoff, J. J. Cell Biol. (2002) [Pubmed]
  15. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Tickenbrock, L., Schwäble, J., Wiedehage, M., Steffen, B., Sargin, B., Choudhary, C., Brandts, C., Berdel, W.E., Müller-Tidow, C., Serve, H. Blood (2005) [Pubmed]
  16. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Singh, R., Artaza, J.N., Taylor, W.E., Braga, M., Yuan, X., Gonzalez-Cadavid, N.F., Bhasin, S. Endocrinology (2006) [Pubmed]
  17. Genetic and cellular characterizations of human TCF4 with microsatellite instability in colon cancer and leukemia cell lines. Chang, H.R., Cheng, T.L., Liu, T.Z., Hu, H.S., Hsu, L.S., Tseng, W.C., Chen, C.H., Tsao, D.A. Cancer Lett. (2006) [Pubmed]
  18. Wnt signalling induces maturation of Paneth cells in intestinal crypts. van Es, J.H., Jay, P., Gregorieff, A., van Gijn, M.E., Jonkheer, S., Hatzis, P., Thiele, A., van den Born, M., Begthel, H., Brabletz, T., Taketo, M.M., Clevers, H. Nat. Cell Biol. (2005) [Pubmed]
  19. Restoration of epithelial cell polarity in a colorectal cancer cell line by suppression of beta-catenin/T-cell factor 4-mediated gene transactivation. Naishiro, Y., Yamada, T., Takaoka, A.S., Hayashi, R., Hasegawa, F., Imai, K., Hirohashi, S. Cancer Res. (2001) [Pubmed]
  20. Nuclear translocations of beta-catenin and TCF4 in gastric cancers correlate with lymph node metastasis but probably not with CD44 expression. Chen, X.Y., Wang, Z.C., Li, H., Cheng, X.X., Sun, Y., Wang, X.W., Wu, M.L., Liu, J. Hum. Pathol. (2005) [Pubmed]
  21. Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability. Shimizu, Y., Ikeda, S., Fujimori, M., Kodama, S., Nakahara, M., Okajima, M., Asahara, T. Genes Chromosomes Cancer (2002) [Pubmed]
  22. The human D-glucuronyl C5-epimerase gene is transcriptionally activated through the beta-catenin-TCF4 pathway. Ghiselli, G., Agrawal, A. Biochem. J. (2005) [Pubmed]
  23. Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling. Rao, A.S., Kremenevskaja, N., Resch, J., Brabant, G. Eur. J. Endocrinol. (2005) [Pubmed]
  24. Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Marotta, A., Tan, C., Gray, V., Malik, S., Gallinger, S., Sanghera, J., Dupuis, B., Owen, D., Dedhar, S., Salh, B. Oncogene (2001) [Pubmed]
  25. Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). Chakrabarty, S., Wang, H., Canaff, L., Hendy, G.N., Appelman, H., Varani, J. Cancer Res. (2005) [Pubmed]
  26. Thermodynamics of the high-affinity interaction of TCF4 with beta-catenin. Knapp, S., Zamai, M., Volpi, D., Nardese, V., Avanzi, N., Breton, J., Plyte, S., Flocco, M., Marconi, M., Isacchi, A., Caiolfa, V.R. J. Mol. Biol. (2001) [Pubmed]
  27. Heregulin induces expression, DNA binding activity, and transactivating functions of basic leucine zipper activating transcription factor 4. Talukder, A.H., Vadlamudi, R., Mandal, M., Kumar, R. Cancer Res. (2000) [Pubmed]
  28. Evolution of vertebrate E protein transcription factors: comparative analysis of the E protein gene family in Takifugu rubripes and humans. Hikima, J., Lennard, M.L., Wilson, M.R., Miller, N.W., Clem, L.W., Warr, G.W. Physiol. Genomics (2005) [Pubmed]
  29. A mammalian two-hybrid system for adenomatous polyposis coli-mutated colon cancer therapeutics. Wakita, K., Tetsu, O., McCormick, F. Cancer Res. (2001) [Pubmed]
  30. beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Brabletz, T., Jung, A., Dag, S., Hlubek, F., Kirchner, T. Am. J. Pathol. (1999) [Pubmed]
  31. Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells. Mizushima, T., Nakagawa, H., Kamberov, Y.G., Wilder, E.L., Klein, P.S., Rustgi, A.K. Cancer Res. (2002) [Pubmed]
  32. A comparative evaluation of beta-catenin and plakoglobin signaling activity. Williams, B.O., Barish, G.D., Klymkowsky, M.W., Varmus, H.E. Oncogene (2000) [Pubmed]
  33. Hot spots in Tcf4 for the interaction with beta-catenin. Fasolini, M., Wu, X., Flocco, M., Trosset, J.Y., Oppermann, U., Knapp, S. J. Biol. Chem. (2003) [Pubmed]
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