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Gene Review

Tcf3  -  transcription factor 3

Mus musculus

Synonyms: A1, AA408400, ALF2, AW209082, Alf2, ...
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Disease relevance of Tcfe2a


Psychiatry related information on Tcfe2a

  • MyoD activity was also inhibited by Id, a HLH protein, and this inhibition was reversed by the addition of excess E12 or MITF-2A [6].

High impact information on Tcfe2a


Chemical compound and disease context of Tcfe2a

  • A fusion construct composed of E2A and the Escherichia coli DNA adenosine methyltransferase (E47Dam) was subcloned in lentivirus vectors and used to transduce precursor B-cell and myeloid progenitor cell lines [11].
  • The chloramphenicol acetyltransferase gene under the control of the late E2A promoter of adenovirus type 2 (Ad2) was introduced as transgene into the B6D2F1 mouse strain with mixed genetic background and became extensively de novo methylated [12].
  • There was also a transient twofold increase in mrf4 transcripts by dexamethasone treatment in dividing cells, while no changes were detected in the levels of Id, E12, or TnC messages [13].
  • Diallyl sulfide (DAS), an inhibitor of CYP2E1, also protected against the cisplatin toxicity in the E47 cells [14].
  • The early expression of voltage-activated chloride channels of large unitary conductance (450 pS in symmetrical 140 mM KCl) was demonstrated using patch-clamp techniques in two preparations: (i) neural crest cells isolated from 9-day-old (E9) mouse embryos and (ii) acutely isolated dorsal root ganglion cells isolated from E12 mouse embryos [15].

Biological context of Tcfe2a


Anatomical context of Tcfe2a


Associations of Tcfe2a with chemical compounds


Physical interactions of Tcfe2a

  • Interaction assays in yeast and in vitro demonstrate that MATH4A interacts efficiently with both MASH1 and the ubiquitous bHLH protein E12 [27].
  • However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway [21].
  • Retroviral transduction of Id3 also repressed the SRG3 expression by inhibiting the E box binding activity of the E2A/HEB complex [28].
  • The age-related decrease in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrow-derived B cell precursors [29].
  • Gel mobility shift assays demonstrate that Twist can bind to the muscle creatine kinase E-box and inhibit DNA binding of heterodimers of E12 with myogenic bHLH transcription factors like MyoD [30].

Enzymatic interactions of Tcfe2a


Regulatory relationships of Tcfe2a

  • The capacity to respond to SCF may influence the levels of E2A during B-cell development [23].
  • Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation [32].
  • We next investigated the signal transduction pathways controlling E2A mRNA expression and stability and found that p38 MAPK regulates E2A mRNA expression through increased mRNA stability and is down-regulated in aged activated B cells [33].
  • Transcriptional repression by Fos and Jun is specific to myogenic HLH proteins and is not observed with the widely expressed HLH protein E47, which recognizes the same DNA sequence [34].
  • These observations support a model in which the upregulation of pre-TCR signalling seems to be the prerequi-site for Notch3-induced inhibition of E2A, thus leading to the development of lymphoma in Notch3 transgenic mice [35].

Other interactions of Tcfe2a

  • These data suggest a molecular basis for the hierarchical dependence of Pax5 function on EBF and E2A in B lymphocyte development [36].
  • EBF and the basic helix-loop-helix transcription factor E47 each contributed to epigenetic modifications of the mb-1 promoter, including CpG demethylation and nucleosomal remodeling [36].
  • These findings identify a novel pro-myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis [37].
  • When E47 lacking the HLH domain was overexpressed, Id could no longer reverse growth inhibition [19].
  • IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors [38].

Analytical, diagnostic and therapeutic context of Tcfe2a

  • We have now generated E2A (-/-) mice by gene targeting [10].
  • Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system [39].
  • To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein [32].
  • We also obtained evidence for extensive collaborative actions of EBF and E47 even though microarray analysis of hematopoetic progenitor cells ectopically expressing these proteins suggested that they activated only a subset of pre-B cell restricted genes [40].
  • From titrations of MyoD-dansyl with E12 at 100 mM KCl, a free energy of heterodimerization of 8.7 (+0.4/-2.4) kcal/mol was recovered using rigorous confidence limit testing [41].


  1. Disruption of pre-TCR expression accelerates lymphomagenesis in E2A-deficient mice. Engel, I., Murre, C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Feldman, B.J., Hampton, T., Cleary, M.L. Blood (2000) [Pubmed]
  3. Purification of E. coli-synthesized Pan proteins and development of a Pan-specific monoclonal antibody. Vierra, C.A., Xin, X.Q., Jacobs, Y.T., Campbell, J.M., Shen, L.P., Rutter, W.J., Nelson, C. Hybridoma (1994) [Pubmed]
  4. Expression patterns of the hepatic leukemia factor gene in the nervous system of developing and adult mice. Hitzler, J.K., Soares, H.D., Drolet, D.W., Inaba, T., O'Connel, S., MG Rosenfeld, n.u.l.l., Morgan, J.I., Look, A.T. Brain Res. (1999) [Pubmed]
  5. Gradient of E2A activity in B-cell development. Herblot, S., Aplan, P.D., Hoang, T. Mol. Cell. Biol. (2002) [Pubmed]
  6. A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity. Skerjanc, I.S., Truong, J., Filion, P., McBurney, M.W. J. Biol. Chem. (1996) [Pubmed]
  7. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Silva, J.P., Köhler, M., Graff, C., Oldfors, A., Magnuson, M.A., Berggren, P.O., Larsson, N.G. Nat. Genet. (2000) [Pubmed]
  8. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Larsson, N.G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G.S., Clayton, D.A. Nat. Genet. (1998) [Pubmed]
  9. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Okuda, T., van Deursen, J., Hiebert, S.W., Grosveld, G., Downing, J.R. Cell (1996) [Pubmed]
  10. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Bain, G., Maandag, E.C., Izon, D.J., Amsen, D., Kruisbeek, A.M., Weintraub, B.C., Krop, I., Schlissel, M.S., Feeney, A.J., van Roon, M. Cell (1994) [Pubmed]
  11. Identification of cyclin D3 as a direct target of E2A using DamID. Song, S., Cooperman, J., Letting, D.L., Blobel, G.A., Choi, J.K. Mol. Cell. Biol. (2004) [Pubmed]
  12. Epigenetic and genotype-specific effects on the stability of de novo imposed methylation patterns in transgenic mice. Schumacher, A., Koetsier, P.A., Hertz, J., Doerfler, W. J. Biol. Chem. (2000) [Pubmed]
  13. Dexamethasone-mediated induction of MMTV-myf5 in DD3 myoblasts increases endogenous myogenin expression but does not transactivate myf5. Arnold, T.E., Worrell, R.A., Barth, J.L., Morris, J., Ivarie, R. Exp. Cell Res. (1994) [Pubmed]
  14. Cisplatin-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 2E1. Lu, Y., Cederbaum, A.I. Toxicol. Sci. (2006) [Pubmed]
  15. Large unit conductance voltage chloride channels are expressed in mouse neural crest cells and embryonic dorsal root ganglion cells. Rabasseda, X., Valmier, J., Larmet, Y., Simonneau, M. Brain Res. Dev. Brain Res. (1990) [Pubmed]
  16. Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. Ikawa, T., Kawamoto, H., Wright, L.Y., Murre, C. Immunity (2004) [Pubmed]
  17. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. Seet, C.S., Brumbaugh, R.L., Kee, B.L. J. Exp. Med. (2004) [Pubmed]
  18. Thymocyte maturation is regulated by the activity of the helix-loop-helix protein, E47. Bain, G., Quong, M.W., Soloff, R.S., Hedrick, S.M., Murre, C. J. Exp. Med. (1999) [Pubmed]
  19. Regulation of G1 progression by E2A and Id helix-loop-helix proteins. Peverali, F.A., Ramqvist, T., Saffrich, R., Pepperkok, R., Barone, M.V., Philipson, L. EMBO J. (1994) [Pubmed]
  20. Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. O'Riordan, M., Grosschedl, R. Immunity (1999) [Pubmed]
  21. Early thymocyte development is regulated by modulation of E2A protein activity. Engel, I., Johns, C., Bain, G., Rivera, R.R., Murre, C. J. Exp. Med. (2001) [Pubmed]
  22. Notch-induced E2A ubiquitination and degradation are controlled by MAP kinase activities. Nie, L., Xu, M., Vladimirova, A., Sun, X.H. EMBO J. (2003) [Pubmed]
  23. Levels of E2A protein expression in B cell precursors are stage-dependent and inhibited by stem cell factor (c-kit ligand). Riley, R.L., Knowles, J., King, A.M. Exp. Hematol. (2002) [Pubmed]
  24. Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching. Murayama, A., Kim, M.S., Yanagisawa, J., Takeyama, K., Kato, S. EMBO J. (2004) [Pubmed]
  25. Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. Van der Put, E., Frasca, D., King, A.M., Blomberg, B.B., Riley, R.L. J. Immunol. (2004) [Pubmed]
  26. Critical role for a single leucine residue in leukemia induction by E2A-PBX1. Bayly, R., Murase, T., Hyndman, B.D., Savage, R., Nurmohamed, S., Munro, K., Casselman, R., Smith, S.P., LeBrun, D.P. Mol. Cell. Biol. (2006) [Pubmed]
  27. Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors. Gradwohl, G., Fode, C., Guillemot, F. Dev. Biol. (1996) [Pubmed]
  28. E2A/HEB and Id3 proteins control the sensitivity to glucocorticoid-induced apoptosis in thymocytes by regulating the SRG3 expression. Ko, M., Ahn, J., Lee, C., Chung, H., Jeon, S.H., Chung, H.Y., Seong, R.H. J. Biol. Chem. (2004) [Pubmed]
  29. The age-related decrease in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrow-derived B cell precursors. Frasca, D., Nguyen, D., Van der Put, E., Riley, R.L., Blomberg, B.B. Front. Biosci. (2003) [Pubmed]
  30. Repression of muscle-specific gene activation by the murine Twist protein. Hebrok, M., Füchtbauer, A., Füchtbauer, E.M. Exp. Cell Res. (1997) [Pubmed]
  31. MEKK1 signaling through p38 leads to transcriptional inactivation of E47 and repression of skeletal myogenesis. Page, J.L., Wang, X., Sordillo, L.M., Johnson, S.E. J. Biol. Chem. (2004) [Pubmed]
  32. Notch-induced E2A degradation requires CHIP and Hsc70 as novel facilitators of ubiquitination. Huang, Z., Nie, L., Xu, M., Sun, X.H. Mol. Cell. Biol. (2004) [Pubmed]
  33. RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. Frasca, D., Van der Put, E., Landin, A.M., Gong, D., Riley, R.L., Blomberg, B.B. J. Immunol. (2005) [Pubmed]
  34. Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression. Li, L., Chambard, J.C., Karin, M., Olson, E.N. Genes Dev. (1992) [Pubmed]
  35. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma. Talora, C., Campese, A.F., Bellavia, D., Pascucci, M., Checquolo, S., Groppioni, M., Frati, L., von Boehmer, H., Gulino, A., Screpanti, I. EMBO Rep. (2003) [Pubmed]
  36. Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Maier, H., Ostraat, R., Gao, H., Fields, S., Shinton, S.A., Medina, K.L., Ikawa, T., Murre, C., Singh, H., Hardy, R.R., Hagman, J. Nat. Immunol. (2004) [Pubmed]
  37. E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. Lluís, F., Ballestar, E., Suelves, M., Esteller, M., Muñoz-Cánoves, P. EMBO J. (2005) [Pubmed]
  38. IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors. Kee, B.L., Bain, G., Murre, C. EMBO J. (2002) [Pubmed]
  39. Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system. Greenbaum, S., Zhuang, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  40. Pearson correlation analysis of microarray data allows for the identification of genetic targets for early B-cell factor. Månsson, R., Tsapogas, P., Akerlund, M., Lagergren, A., Gisler, R., Sigvardsson, M. J. Biol. Chem. (2004) [Pubmed]
  41. MyoD-E12 heterodimers and MyoD-MyoD homodimers are equally stable. Maleki, S.J., Royer, C.A., Hurlburt, B.K. Biochemistry (1997) [Pubmed]
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