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Gene Review

TCF3  -  transcription factor 3

Homo sapiens

Synonyms: BHLHB21, Class B basic helix-loop-helix protein 21, E2A, E47, ITF1, ...
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Disease relevance of TCF3


Psychiatry related information on TCF3


High impact information on TCF3

  • The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis [8].
  • Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX [9].
  • The Tcf3-CBD forms an elongated structure with three binding modules that runs antiparallel to beta-catenin along the positively charged groove formed by the armadillo repeats [10].
  • These results suggest a novel mechanism for regulating the dimerization status and DNA binding properties of E2A HLH transcription factors [11].
  • When the disulfide bond is reduced by an activity present in muscle cell lysates or disrupted by site-directed mutagenesis, the monomeric form of the protein is strongly favored at 37 degrees C. These E2A monomers cannot bind DNA but heterodimerize efficiently with Id and MyoD [11].

Chemical compound and disease context of TCF3


Biological context of TCF3


Anatomical context of TCF3

  • Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells [3].
  • Furthermore, a heterodimeric complex containing ABF-1 and E2A can be detected in EBV-immortalized lymphoblastoid cell lines [21].
  • The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells [20].
  • Expression of E2A and FGFR3 was seen at the location of osteoblast differentiation in the calvaria of mouse embryos, implicating bHLH molecules in physiological osteoblast differentiation [22].
  • Immunohistochemistry of placental tissues and differentiating villous explant cultures showed that expression of TCF-3/4 strongly increased in invading trophoblasts [23].

Associations of TCF3 with chemical compounds

  • Fourth, C3H10T1/2 cells expressing antisense E2A transcripts contain low levels of E2A gene products and display less terminal muscle differentiation when infected with retroviral MyoD or when challenged to differentiate with 5-azacytidine treatment [24].
  • HEN1 encodes a 20-kDa polypeptide (pp20HEN1) that is phosphorylated exclusively at serine residues and forms dimeric bHLH complexes either by self-association or by heterologous interaction with the E2A gene products (E12 or E47) [25].
  • Moreover, overexpression of 31-kDa led to cell death that could be inhibited by treatment with the caspase inhibitor ZVAD-fluoromethyl ketone or by ectopic expression of E2A or p21(Waf1/Cip1) [26].
  • The coactivator Bridge-1 (PSMD9) regulates the transcriptional activation of glucose-responsive enhancers in the insulin gene in a dose-dependent manner via PDZ domain-mediated interactions with E2A transcription factors [27].
  • Moreover, in cell line HE2, the integrated, heavily methylated late E2A promoter has been shown by the genomic sequencing technique to contain 5-methyldeoxycytidine residues, not only in all 5'-CG-3' dinucleotides but also in a 5'CA-3' and a 5'-CT-3' dinucleotide sequence [28].

Physical interactions of TCF3

  • The gene (E2A) for enhancer binding transcription factors E12 and E47 maps to the t(1;19) chromosomal translocation breakpoint in pre-B cell leukemias [29].
  • The t(1;19) translocation results in the production of a chimeric transcription factor containing the N-terminal transactivation domain of E2A fused to the C-terminal DNA-binding homeodomain of Pbx1 [30].
  • These differences were directly attributable to loss of an HLF ancillary DNA-binding domain in all E2A-HLF chimeras and were further exacerbated by a zipper mutation in one isolate [31].
  • These two transcription factors can recognize the same DNA motif in the adenovirus E2A promoter and can bind to it by themselves or in association with RB [32].
  • Competition experiments revealed that these three classes are functionally equivalent to each other and to the E2F/DRTF-1 binding site in the adenovirus E2A promoter [32].

Regulatory relationships of TCF3

  • We found that the minimal p21/waf1 promoter (-49 to +49 sequence) was activated by Tax and the minimal promoter contained two E2A transcription factor binding sites located between the TATA box and the initiation site [33].
  • Expression of BHLHB1 dramatically inhibited E2A-mediated transcription activation in NIH 3T3 fibroblasts and Jurkat T cells [34].
  • TFE3 can only stimulate enhancer activity in the presence of ITF-1 or in the absence of a microE5 motif [35].
  • The inhibition model postulates that Tal1 interferes with the tumor-suppressing function of E2A [36].
  • Finally, cotransfection of rPM-Scl and E47 specifically increased the promoter activity of a luciferase reporter construct containing an E box and did not affect the basal activity of the reporter construct. rPM-Scl appears to be a novel non-HLH-interacting partner of E12/E47 that regulates E2A protein transcription [37].

Other interactions of TCF3

  • The complementary DNAs are the products of distinct genes, yet both ITF-1 and ITF-2 are structurally and functionally similar [19].
  • Thus, the malignant properties of TAL1 may be due to obligate interaction with the E2A polypeptides [3].
  • Separate expression of BETA2, E2A, or PDX1 led to modest (<10-fold) activation of the insulin promoter, whereas co-expression of the three proteins produced synergistic, high level activation (160-fold) [38].
  • Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter [38].
  • The 19p13 breakpoint of one tumor was mapped to a location between the INSR and the TCF3 loci [2].

Analytical, diagnostic and therapeutic context of TCF3


  1. Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors. Amini Nik, S., Hohenstein, P., Jadidizadeh, A., Van Dam, K., Bastidas, A., Berry, R.L., Patek, C.E., Van der Schueren, B., Cassiman, J.J., Tejpar, S. Int. J. Cancer (2005) [Pubmed]
  2. Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci. Aman, P., Pejovic, T., Wennborg, A., Heim, S., Mitelman, F. Genes Chromosomes Cancer (1993) [Pubmed]
  3. Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. Hsu, H.L., Wadman, I., Baer, R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  4. Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Matsunaga, T., Inaba, T., Matsui, H., Okuya, M., Miyajima, A., Inukai, T., Funabiki, T., Endo, M., Look, A.T., Kurosawa, H. Blood (2004) [Pubmed]
  5. E2A basic helix-loop-helix transcription factors in human leukemia. LeBrun, D.P. Front. Biosci. (2003) [Pubmed]
  6. Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas. Xu, W., Kee, B.L. Blood (2007) [Pubmed]
  7. Coordinate expression and developmental role of Id2 protein and TAL1/E2A heterodimer in erythroid progenitor differentiation. Condorelli, G., Vitelli, L., Valtieri, M., Marta, I., Montesoro, E., Lulli, V., Baer, R., Peschle, C. Blood (1995) [Pubmed]
  8. Transcriptional control of early B cell development. Busslinger, M. Annu. Rev. Immunol. (2004) [Pubmed]
  9. Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. Korsmeyer, S.J. Annu. Rev. Immunol. (1992) [Pubmed]
  10. Crystal structure of a beta-catenin/Tcf complex. Graham, T.A., Weaver, C., Mao, F., Kimelman, D., Xu, W. Cell (2000) [Pubmed]
  11. An intermolecular disulfide bond stabilizes E2A homodimers and is required for DNA binding at physiological temperatures. Benezra, R. Cell (1994) [Pubmed]
  12. Lymphoid-specific expression of the Id3 gene in hematopoietic cells. Selective antagonism of E2A basic helix-loop-helix protein associated with Id3-induced differentiation of erythroleukemia cells. Deed, R.W., Jasiok, M., Norton, J.D. J. Biol. Chem. (1998) [Pubmed]
  13. Overexpression of E2A proteins induces epithelial-mesenchymal transition in human renal proximal tubular epithelial cells suggesting a potential role in renal fibrosis. Slattery, C., McMorrow, T., Ryan, M.P. FEBS Lett. (2006) [Pubmed]
  14. Enhanced binding of HLF/DBP heterodimers represents one mechanism of PAR protein transactivation of the factor VIII and factor IX genes. Begbie, M., Mueller, C., Lillicrap, D. DNA Cell Biol. (1999) [Pubmed]
  15. E1A control of gene expression is mediated by sequences 5' to the transcriptional starts of the early viral genes. Weeks, D.L., Jones, N.C. Mol. Cell. Biol. (1983) [Pubmed]
  16. Reactivation of a methylation-silenced gene in adenovirus-transformed cells by 5-azacytidine or by E1A trans activation. Knust, B., Brüggemann, U., Doerfler, W. J. Virol. (1989) [Pubmed]
  17. Genomic organization and chromosome localization to band 19p13.3 of the human AES gene: gene product exhibits strong similarity to the N-terminal domain of Drosophila enhancer of Split Groucho protein. Hou, E.W., Li, S.S. DNA Cell Biol. (1998) [Pubmed]
  18. Apoptosis promoted by up-regulation of TFPT (TCF3 fusion partner) appears p53 independent, cell type restricted and cell density influenced. Franchini, C., Fontana, F., Minuzzo, M., Babbio, F., Privitera, E. Apoptosis (2006) [Pubmed]
  19. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Henthorn, P., Kiledjian, M., Kadesch, T. Science (1990) [Pubmed]
  20. DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein. Inaba, T., Shapiro, L.H., Funabiki, T., Sinclair, A.E., Jones, B.G., Ashmun, R.A., Look, A.T. Mol. Cell. Biol. (1994) [Pubmed]
  21. Characterization of ABF-1, a novel basic helix-loop-helix transcription factor expressed in activated B lymphocytes. Massari, M.E., Rivera, R.R., Voland, J.R., Quong, M.W., Breit, T.M., van Dongen, J.J., de Smit, O., Murre, C. Mol. Cell. Biol. (1998) [Pubmed]
  22. Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors. Funato, N., Ohtani, K., Ohyama, K., Kuroda, T., Nakamura, M. Mol. Cell. Biol. (2001) [Pubmed]
  23. Activation of the canonical wingless/t-cell factor signaling pathway promotes invasive differentiation of human trophoblast. Pollheimer, J., Loregger, T., Sonderegger, S., Saleh, L., Bauer, S., Bilban, M., Czerwenka, K., Husslein, P., Knöfler, M. Am. J. Pathol. (2006) [Pubmed]
  24. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Lassar, A.B., Davis, R.L., Wright, W.E., Kadesch, T., Murre, C., Voronova, A., Baltimore, D., Weintraub, H. Cell (1991) [Pubmed]
  25. HEN1 encodes a 20-kilodalton phosphoprotein that binds an extended E-box motif as a homodimer. Brown, L., Baer, R. Mol. Cell. Biol. (1994) [Pubmed]
  26. The 31-kDa caspase-generated cleavage product of p130cas functions as a transcriptional repressor of E2A in apoptotic cells. Kim, W., Kook, S., Kim, D.J., Teodorof, C., Song, W.K. J. Biol. Chem. (2004) [Pubmed]
  27. Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Volinic, J.L., Lee, J.H., Eto, K., Kaur, V., Thomas, M.K. Mol. Endocrinol. (2006) [Pubmed]
  28. Establishment of de novo DNA methylation patterns. Transcription factor binding and deoxycytidine methylation at CpG and non-CpG sequences in an integrated adenovirus promoter. Toth, M., Müller, U., Doerfler, W. J. Mol. Biol. (1990) [Pubmed]
  29. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Nourse, J., Mellentin, J.D., Galili, N., Wilkinson, J., Stanbridge, E., Smith, S.D., Cleary, M.L. Cell (1990) [Pubmed]
  30. Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia. McWhirter, J.R., Neuteboom, S.T., Wancewicz, E.V., Monia, B.P., Downing, J.R., Murre, C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  31. DNA-binding and transcriptional regulatory properties of hepatic leukemia factor (HLF) and the t(17;19) acute lymphoblastic leukemia chimera E2A-HLF. Hunger, S.P., Brown, R., Cleary, M.L. Mol. Cell. Biol. (1994) [Pubmed]
  32. Complexes containing the retinoblastoma gene product recognize different DNA motifs related to the E2F binding site. Ouellette, M.M., Chen, J., Wright, W.E., Shay, J.W. Oncogene (1992) [Pubmed]
  33. Gene expression array of HTLV type 1-infected T cells: Up-regulation of transcription factors and cell cycle genes. de La Fuente, C., Deng, L., Santiago, F., Arce, L., Wang, L., Kashanchi, F. AIDS Res. Hum. Retroviruses (2000) [Pubmed]
  34. The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene. Wang, J., Jani-Sait, S.N., Escalon, E.A., Carroll, A.J., de Jong, P.J., Kirsch, I.R., Aplan, P.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  35. Modulation of the IgH enhancer's cell type specificity through a genetic switch. Ruezinsky, D., Beckmann, H., Kadesch, T. Genes Dev. (1991) [Pubmed]
  36. Growth inhibition and apoptosis due to restoration of E2A activity in T cell acute lymphoblastic leukemia cells. Park, S.T., Nolan, G.P., Sun, X.H. J. Exp. Med. (1999) [Pubmed]
  37. The polymyositis-scleroderma autoantigen interacts with the helix-loop-helix proteins E12 and E47. Kho, C.J., Huggins, G.S., Endege, W.O., Patterson, C., Jain, M.K., Lee, M.E., Haber, E. J. Biol. Chem. (1997) [Pubmed]
  38. Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter. Glick, E., Leshkowitz, D., Walker, M.D. J. Biol. Chem. (2000) [Pubmed]
  39. Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system. Chakraborty, T., Martin, J.F., Olson, E.N. J. Biol. Chem. (1992) [Pubmed]
  40. The t(1;19)(q23;p13) results in consistent fusion of E2A and PBX1 coding sequences in acute lymphoblastic leukemias. Hunger, S.P., Galili, N., Carroll, A.J., Crist, W.M., Link, M.P., Cleary, M.L. Blood (1991) [Pubmed]
  41. E2A expression, nuclear localization, and in vivo formation of DNA- and non-DNA-binding species during B-cell development. Jacobs, Y., Vierra, C., Nelson, C. Mol. Cell. Biol. (1993) [Pubmed]
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