TCF3 explained

Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protein that in humans is encoded by the TCF3 gene.^{[1] [2] [3]} TCF3 has been shown to directly enhance Hes1 (a well-known target of Notch signaling) expression.^[4]

Function

This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription 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 the 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.

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),^[8] childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384).^[1]

Interactions

TCF3 has been shown to interact with:

• CBFA2T3,
• CREBBP,
• ELK3,^[9]
• EP300,
• ID3,^{[10] [11]}
• LDB1,^[12]
• LMX1A,^[13]
• LYL1,^[14]
• MAPKAPK3,^[15]
• MyoD,^{[11] [16]}
• Myogenin,^{[11] [17]}
• PCAF,^[18]
• TAL1^{[12] [19]}
• TWIST1,^[20] and
• UBE2I.^[21]

Further reading

• LeBrun DP . E2A basic helix-loop-helix transcription factors in human leukemia . Frontiers in Bioscience . 8 . 1–3 . s206–s222 . May 2003 . 12700034 . 10.2741/1030 . free .

Notes and References

1. Web site: Entrez Gene: TCF3 .
2. Henthorn P, McCarrick-Walmsley R, Kadesch T . Sequence of the cDNA encoding ITF-1, a positive-acting transcription factor . Nucleic Acids Research . 18 . 3 . 677 . February 1990 . 2308859 . 333499 . 10.1093/nar/18.3.677 .
3. Kamps MP, Murre C, Sun XH, Baltimore D . A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL . Cell . 60 . 4 . 547–555 . February 1990 . 1967983 . 10.1016/0092-8674(90)90658-2 . 39661371 .
4. http://jem.rupress.org/content/203/5/1329.full.pdf E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment
5. Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M . Nine-amino-acid transactivation domain: establishment and prediction utilities . Genomics . 89 . 6 . 756–768 . June 2007 . 17467953 . 10.1016/j.ygeno.2007.02.003 .
6. Piskacek M, Vasku A, Hajek R, Knight A . Shared structural features of the 9aaTAD family in complex with CBP . Molecular BioSystems . 11 . 3 . 844–851 . March 2015 . 25564305 . 10.1039/c4mb00672k . free .
7. Quong MW, Romanow WJ, Murre C . E protein function in lymphocyte development . Annual Review of Immunology . 20 . 301–322 . 2002 . 11861605 . 10.1146/annurev.immunol.20.092501.162048 .
8. Herblot S, Aplan PD, Hoang T . Gradient of E2A activity in B-cell development . Molecular and Cellular Biology . 22 . 3 . 886–900 . February 2002 . 11784864 . 133542 . 10.1128/MCB.22.3.886-900.2002 .
9. Maira SM, Wurtz JM, Wasylyk B . Net (ERP/SAP2) one of the Ras-inducible TCFs, has a novel inhibitory domain with resemblance to the helix-loop-helix motif . The EMBO Journal . 15 . 21 . 5849–5865 . November 1996 . 8918463 . 452333 . 10.1002/j.1460-2075.1996.tb00972.x .
10. Deed RW, Jasiok M, Norton JD . 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 . 8278–8286 . April 1998 . 9525934 . 10.1074/jbc.273.14.8278 . free .
11. Langlands K, Yin X, Anand G, Prochownik EV . Differential interactions of Id proteins with basic-helix-loop-helix transcription factors . The Journal of Biological Chemistry . 272 . 32 . 19785–19793 . August 1997 . 9242638 . 10.1074/jbc.272.32.19785 . free .
12. Goardon N, Lambert JA, Rodriguez P, Nissaire P, Herblot S, Thibault P, Dumenil D, Strouboulis J, Romeo PH, Hoang T . ETO2 coordinates cellular proliferation and differentiation during erythropoiesis . The EMBO Journal . 25 . 2 . 357–366 . January 2006 . 16407974 . 1383517 . 10.1038/sj.emboj.7600934 .
13. Johnson JD, Zhang W, Rudnick A, Rutter WJ, German MS . Transcriptional synergy between LIM-homeodomain proteins and basic helix-loop-helix proteins: the LIM2 domain determines specificity . Molecular and Cellular Biology . 17 . 7 . 3488–3496 . July 1997 . 9199284 . 232202 . 10.1128/mcb.17.7.3488 .
14. Miyamoto A, Cui X, Naumovski L, Cleary ML . Helix-loop-helix proteins LYL1 and E2a form heterodimeric complexes with distinctive DNA-binding properties in hematolymphoid cells . Molecular and Cellular Biology . 16 . 5 . 2394–2401 . May 1996 . 8628307 . 231228 . 10.1128/mcb.16.5.2394 .
15. Neufeld B, Grosse-Wilde A, Hoffmeyer A, Jordan BW, Chen P, Dinev D, Ludwig S, Rapp UR . 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 . 20239–20242 . July 2000 . 10781029 . 10.1074/jbc.C901040199 . free .
16. Maleki SJ, Royer CA, Hurlburt BK . MyoD-E12 heterodimers and MyoD-MyoD homodimers are equally stable . Biochemistry . 36 . 22 . 6762–6767 . June 1997 . 9184158 . 10.1021/bi970262m .
17. Chakraborty T, Martin JF, Olson EN . Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system . The Journal of Biological Chemistry . 267 . 25 . 17498–17501 . September 1992 . 1325437 . 10.1016/S0021-9258(19)37069-3 . free .
18. Bradney C, Hjelmeland M, Komatsu Y, Yoshida M, Yao TP, Zhuang Y . Regulation of E2A activities by histone acetyltransferases in B lymphocyte development . The Journal of Biological Chemistry . 278 . 4 . 2370–2376 . January 2003 . 12435739 . 10.1074/jbc.M211464200 . free .
19. Hsu HL, Wadman I, Baer R . Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells . Proceedings of the National Academy of Sciences of the United States of America . 91 . 8 . 3181–3185 . April 1994 . 8159721 . 43539 . 10.1073/pnas.91.8.3181 . free . 1994PNAS...91.3181H .
20. El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J . Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location . Human Molecular Genetics . 9 . 5 . 813–819 . March 2000 . 10749989 . 10.1093/hmg/9.5.813 . free .
21. Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME . Characterization of the mUBC9-binding sites required for E2A protein degradation . The Journal of Biological Chemistry . 274 . 40 . 28690–28696 . October 1999 . 10497239 . 10.1074/jbc.274.40.28690 . free .