Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protein that in humans is encoded by the TCF3gene.[1][2][3] TCF3 has been shown to directly enhance Hes1 (a well-known target of Notch signaling) expression.[4]
This gene encodes a member of the E protein (class I) family of helix-loop-helixtranscription factors. The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP.[5][6] E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development.[1]
This gene regulates many developmental patterning processes such as lymphocyte and central nervous system (CNS) development. E proteins are involved in the development of lymphocytes.[7] They initiate transcription by binding to regulatory E-box sequences on target genes. Additionally, development of the neocortex of the brain is controlled in part by a Wnt signaling pathway. This pathway is essential for proper neuronal differentiation and proliferation of neural precursor cells. However, Wnt must be suppressed until it is the appropriate time in development to initiate neuronal differentiation and proliferation of neural precursor cells.[8] The TCF3 gene has been shown to play a role in suppressing Wnt for this purpose. Furthermore, TCF3 has been shown to represses β-catenin in this pathway as well.[9] Undifferentiated neural precursor cells contain high expression of TCF3, but as those cells become more differentiated, the expression of TCF3 decreases. Therefore, lack of TCF3 increases neural precursor cell reprogramming and greater expression of TCF3 suppresses reprogramming of neural precursor cells.[9] In a TCF3 knock out model in mice, the mesoderm forms, but the structures of the mesoderm, specifically structures of the CNS, are duplicated. Therefore, repressive functions of TCF3 are necessary for proper anterior-posterior axis development.[10]
Clinical significance
Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1 and t(17;19), with HLF),[11] childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384).[1]
↑Piskacek, S (2007). "Nine-amino-acid transactivation domain: Establishment and prediction utilities". Genomics. 89: 756–768. doi:10.1016/j.ygeno.2007.02.003. PMID17467953.
↑Piskacek, Martin; Vasku, A; Hajek, R; Knight, A (2015). "Shared structural features of the 9aaTAD family in complex with CBP". Mol Biosyst. 11: 844–851. doi:10.1039/c4mb00672k. PMID25564305.
↑Merrill BJ, Pasolli HA, Polak L, Rendl M, García-García MJ, Anderson KV, Fuchs E (Jan 2004). "Tcf3: a transcriptional regulator of axis induction in the early embryo". Development. 131 (2): 263–74. doi:10.1242/dev.00935. PMID14668413.
↑ 13.013.113.2Bradney C, Hjelmeland M, Komatsu Y, Yoshida M, Yao TP, Zhuang Y (Jan 2003). "Regulation of E2A activities by histone acetyltransferases in B lymphocyte development". The Journal of Biological Chemistry. 278 (4): 2370–6. doi:10.1074/jbc.M211464200. PMID12435739.
↑Deed RW, Jasiok M, Norton JD (Apr 1998). "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". The Journal of Biological Chemistry. 273 (14): 8278–86. doi:10.1074/jbc.273.14.8278. PMID9525934.
↑ 16.016.116.2Langlands K, Yin X, Anand G, Prochownik EV (Aug 1997). "Differential interactions of Id proteins with basic-helix-loop-helix transcription factors". The Journal of Biological Chemistry. 272 (32): 19785–93. doi:10.1074/jbc.272.32.19785. PMID9242638.
↑Neufeld B, Grosse-Wilde A, Hoffmeyer A, Jordan BW, Chen P, Dinev D, Ludwig S, Rapp UR (Jul 2000). "Serine/Threonine kinases 3pK and MAPK-activated protein kinase 2 interact with the basic helix-loop-helix transcription factor E47 and repress its transcriptional activity". The Journal of Biological Chemistry. 275 (27): 20239–42. doi:10.1074/jbc.C901040199. PMID10781029.
↑Maleki SJ, Royer CA, Hurlburt BK (Jun 1997). "MyoD-E12 heterodimers and MyoD-MyoD homodimers are equally stable". Biochemistry. 36 (22): 6762–7. doi:10.1021/bi970262m. PMID9184158.
↑Chakraborty T, Martin JF, Olson EN (Sep 1992). "Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system". The Journal of Biological Chemistry. 267 (25): 17498–501. PMID1325437.
↑El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J (Mar 2000). "Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location". Human Molecular Genetics. 9 (5): 813–9. doi:10.1093/hmg/9.5.813. PMID10749989.
↑Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME (Oct 1999). "Characterization of the mUBC9-binding sites required for E2A protein degradation". The Journal of Biological Chemistry. 274 (40): 28690–6. doi:10.1074/jbc.274.40.28690. PMID10497239.
Further reading
LeBrun DP (May 2003). "E2A basic helix-loop-helix transcription factors in human leukemia". Frontiers in Bioscience. 8 (1–3): s206–22. doi:10.2741/1030. PMID12700034.
