The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

E2F4  -  E2F transcription factor 4, p107/p130-binding

Homo sapiens

Synonyms: E2F-4, Transcription factor E2F4
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of E2F4


High impact information on E2F4

  • Previously known as the ultimate recipients of cdk regulatory signals, E2F4/5 and p107 act here as transducers of TGFbeta receptor signals upstream of cdk [5].
  • Among approximately 1200 genes expressed during cell cycle entry, we found that the promoters of 127 were bound by the E2F4 transcription factor in primary fibroblasts [6].
  • Probing a human CpG microarray with chromatin immunoprecipitated using an antibody to E2F4, we have identified 68 unique target loci; 15% are bidirectional promoters and 25% recruit E2F via a mechanism distinct from the defined consensus site [7].
  • E2F4 and DP2 interact through an extensive protein-protein interface, and structural features of this interface suggest it contributes to the preference for heterodimers over homodimers in DNA binding [8].
  • The asymmetry in the extended binding site TTTc/gGCGCc/g is associated with an amino-terminal extension of E2F4, in which an arginine binds in the minor groove near the TTT stretch [8].

Chemical compound and disease context of E2F4


Biological context of E2F4

  • We found that p130 and E2F4 cooperatively repress a common set of genes under each growth arrest condition and showed that growth arrest is achieved through repression of a core set of genes involved not only in cell cycle control but also mitochondrial biogenesis and metabolism [12].
  • We also show that in quiescent normal human cells this entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with both RB family members and E2F4 in a limited number of discrete regions of the nucleus that in other studies have been shown to represent the initial origins of DNA replication following growth stimulation [13].
  • Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells [14].
  • To test the functional implications of these observations, we transfected HaCaT keratinocytes with plasmids coding for E2F1 and E2F4 [15].
  • Concomitant with its redistribution, the apparent molecular weight of total and p107-associated E2F4 increased, at least partially as a result of protein phosphorylation [1].

Anatomical context of E2F4

  • By gel shift analysis, we show that in mitogen-dependent normal melanocytes, external growth factors tightly controlled the levels of growth-promoting free E2F DNA binding activity, composed largely of E2F2 and E2F4, and the growth-suppressive E2F4-p130 complexes [16].
  • In contrast, overexpression of E2F2 or E2F3a results in only a marginal delay of chondrocyte maturation, and increased E2F4 levels have no effect [17].
  • Opposite functions for E2F1 and E2F4 in human epidermal keratinocyte differentiation [15].
  • We also observed an increase in electrophoretic mobility of the predominant E2F components, DP1 and E2F4, as B-lymphocytes progressed from G0 into early G1 [18].
  • E2F1 induces PPARgamma transcription during clonal expansion, whereas E2F4 represses PPARgamma expression during terminal adipocyte differentiation [19].

Associations of E2F4 with chemical compounds


Physical interactions of E2F4

  • Free E2F4 was found to be the predominant species bound to the E2F sites in proliferating cells [25].
  • The E2F4/p130 pocket protein complex emerges as a new target of radiation in prostate carcinoma cells [14].
  • In a first series of experiments, we showed that pRb2/p130 and p107 are not evenly distributed within the nucleus and that cell cycle-dependent binding with E2F4 changes also as a function of their subnuclear localization [26].
  • Genomic signature tags designating putative beta-catenin-binding sites mapped to the 3'-untranslated region (3'-UTR) of the E2F4 gene [27].

Regulatory relationships of E2F4


Other interactions of E2F4

  • E2F-4, a new member of the E2F transcription factor family, interacts with p107 [30].
  • These findings suggest that E2F-4 and E2F-5 may contribute to the regulation of early G1 events including the G0/G1 transition [31].
  • Here we describe the characterization of cDNAs encoding two unusual E2Fs, E2F-4 and E2F-5, each identified by the ability of their gene product to interact with p130 in a yeast two-hybrid system [31].
  • E2F-1 but not E2F-4 can overcome p16-induced G1 cell-cycle arrest [32].
  • The expression levels of cyclin D1, E2F1, and E2F4 in B[a]P-treated transfectants were lower than those in B[a]P-treated HELF cells [21].

Analytical, diagnostic and therapeutic context of E2F4


  1. Herpes simplex virus induces intracellular redistribution of E2F4 and accumulation of E2F pocket protein complexes. Olgiate, J., Ehmann, G.L., Vidyarthi, S., Hilton, M.J., Bachenheimer, S.L. Virology (1999) [Pubmed]
  2. Functional interaction between E2F-4 and p130: evidence for distinct mechanisms underlying growth suppression by different retinoblastoma protein family members. Vairo, G., Livingston, D.M., Ginsberg, D. Genes Dev. (1995) [Pubmed]
  3. Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Lu, Z., Luo, R.Z., Peng, H., Rosen, D.G., Atkinson, E.N., Warneke, C., Huang, M., Nishmoto, A., Liu, J., Liao, W.S., Yu, Y., Bast, R.C. Clin. Cancer Res. (2006) [Pubmed]
  4. Mutations of the E2F4 gene in hematological malignancies having microsatellite instability. Komatsu, N., Takeuchi, S., Ikezoe, T., Tasaka, T., Hatta, Y., Machida, H., Williamson, I.K., Bartram, C.R., Koeffler, H.P., Taguchi, H. Blood (2000) [Pubmed]
  5. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Chen, C.R., Kang, Y., Siegel, P.M., Massagué, J. Cell (2002) [Pubmed]
  6. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Ren, B., Cam, H., Takahashi, Y., Volkert, T., Terragni, J., Young, R.A., Dynlacht, B.D. Genes Dev. (2002) [Pubmed]
  7. Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Weinmann, A.S., Yan, P.S., Oberley, M.J., Huang, T.H., Farnham, P.J. Genes Dev. (2002) [Pubmed]
  8. Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Zheng, N., Fraenkel, E., Pabo, C.O., Pavletich, N.P. Genes Dev. (1999) [Pubmed]
  9. Posttranslational mechanisms contribute to the suppression of specific cyclin:CDK complexes by all-trans retinoic acid in human bronchial epithelial cells. Sueoka, N., Lee, H.Y., Walsh, G.L., Hong, W.K., Kurie, J.M. Cancer Res. (1999) [Pubmed]
  10. N-Acetylcysteine enhances UV-mediated caspase-3 activation, fragmentation of E2F-4, and apoptosis in human C8161 melanoma: inhibition by ectopic Bcl-2 expression. Rieber, M., Rieber, M.S. Biochem. Pharmacol. (2003) [Pubmed]
  11. Microsatellite instability and alteration of E2F-4 gene in adenosquamous and squamous cell carcinomas of the stomach. Woo, D.K., Lee, W.A., Kim, Y.I., Kim, W.H. Pathol. Int. (2000) [Pubmed]
  12. A common set of gene regulatory networks links metabolism and growth inhibition. Cam, H., Balciunaite, E., Blais, A., Spektor, A., Scarpulla, R.C., Young, R., Kluger, Y., Dynlacht, B.D. Mol. Cell (2004) [Pubmed]
  13. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Lai, A., Kennedy, B.K., Barbie, D.A., Bertos, N.R., Yang, X.J., Theberge, M.C., Tsai, S.C., Seto, E., Zhang, Y., Kuzmichev, A., Lane, W.S., Reinberg, D., Harlow, E., Branton, P.E. Mol. Cell. Biol. (2001) [Pubmed]
  14. Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. DuPree, E.L., Mazumder, S., Almasan, A. Cancer Res. (2004) [Pubmed]
  15. Opposite functions for E2F1 and E2F4 in human epidermal keratinocyte differentiation. Paramio, J.M., Segrelles, C., Casanova, M.L., Jorcano, J.L. J. Biol. Chem. (2000) [Pubmed]
  16. Deregulated E2F transcriptional activity in autonomously growing melanoma cells. Halaban, R., Cheng, E., Smicun, Y., Germino, J. J. Exp. Med. (2000) [Pubmed]
  17. Constitutive E2F1 overexpression delays endochondral bone formation by inhibiting chondrocyte differentiation. Scheijen, B., Bronk, M., van der Meer, T., Bernards, R. Mol. Cell. Biol. (2003) [Pubmed]
  18. Modulation of E2F complexes during G0 to S phase transition in human primary B-lymphocytes. van der Sman, J., Thomas, N.S., Lam, E.W. J. Biol. Chem. (1999) [Pubmed]
  19. Atypical transcriptional regulators and cofactors of PPARgamma. Miard, S., Fajas, L. International journal of obesity (2005) (2005) [Pubmed]
  20. Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor. Yoshida, K., Inoue, I. Oncogene (2004) [Pubmed]
  21. Vitamin C inhibits benzo[a]pyrene-induced cell cycle changes partly via cyclin D1/E2F pathway in human embryo lung fibroblasts. Gao, A., Liu, B.C., Shit, X.L., Huang, C.S., Jia, X.W., You, B.R., Ye, M., Shen, F.H., Du, H.J. Biomed. Environ. Sci. (2006) [Pubmed]
  22. E2F4 is exported from the nucleus in a CRM1-dependent manner. Gaubatz, S., Lees, J.A., Lindeman, G.J., Livingston, D.M. Mol. Cell. Biol. (2001) [Pubmed]
  23. Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs. Iwaya, T., Maesawa, C., Nishizuka, S., Suzuki, Y., Sakata, K., Sato, N., Ikeda, K., Koeda, K., Ogasawara, S., Otsuka, K., Kimura, Y., Aoki, K., Ishida, K., Saito, K., Tamura, G. Genes Chromosomes Cancer (1998) [Pubmed]
  24. E2F4 deficiency promotes drug-induced apoptosis. Ma, Y., Freeman, S.N., Cress, W.D. Cancer Biol. Ther. (2004) [Pubmed]
  25. Transcriptional repression of the E2F-1 gene by interferon-alpha is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes. Furukawa, Y., Iwase, S., Kikuchi, J., Nakamura, M., Yamada, H., Matsuda, M. Oncogene (1999) [Pubmed]
  26. pRb2/p130 and p107 control cell growth by multiple strategies and in association with different compartments within the nucleus. Zini, N., Trimarchi, C., Claudio, P.P., Stiegler, P., Marinelli, F., Maltarello, M.C., La Sala, D., De Falco, G., Russo, G., Ammirati, G., Maraldi, N.M., Giordano, A., Cinti, C. J. Cell. Physiol. (2001) [Pubmed]
  27. An Antisense Transcript Induced by Wnt/beta-Catenin Signaling Decreases E2F4. Yochum, G.S., Cleland, R., McWeeney, S., Goodman, R.H. J. Biol. Chem. (2007) [Pubmed]
  28. c-myc is a downstream target of the Smad pathway. Yagi, K., Furuhashi, M., Aoki, H., Goto, D., Kuwano, H., Sugamura, K., Miyazono, K., Kato, M. J. Biol. Chem. (2002) [Pubmed]
  29. Host Cell Factor-1 and E2F4 Interact Via Multiple Determinants in Each Protein. Knez, J., Piluso, D., Bilan, P., Capone, J.P. Mol. Cell. Biochem. (2006) [Pubmed]
  30. E2F-4, a new member of the E2F transcription factor family, interacts with p107. Ginsberg, D., Vairo, G., Chittenden, T., Xiao, Z.X., Xu, G., Wydner, K.L., DeCaprio, J.A., Lawrence, J.B., Livingston, D.M. Genes Dev. (1994) [Pubmed]
  31. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Sardet, C., Vidal, M., Cobrinik, D., Geng, Y., Onufryk, C., Chen, A., Weinberg, R.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  32. E2F-1 but not E2F-4 can overcome p16-induced G1 cell-cycle arrest. Mann, D.J., Jones, N.C. Curr. Biol. (1996) [Pubmed]
  33. Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Balciunaite, E., Spektor, A., Lents, N.H., Cam, H., Te Riele, H., Scime, A., Rudnicki, M.A., Young, R., Dynlacht, B.D. Mol. Cell. Biol. (2005) [Pubmed]
  34. DLK1: increased expression in gliomas and associated with oncogenic activities. Yin, D., Xie, D., Sakajiri, S., Miller, C.W., Zhu, H., Popoviciu, M.L., Said, J.W., Black, K.L., Koeffler, H.P. Oncogene (2006) [Pubmed]
  35. Genomic structure and mutation screening of the E2F4 gene in human tumors. Schwemmle, S., Pfeifer, G.P. Int. J. Cancer (2000) [Pubmed]
  36. Distinct capacities of individual E2Fs to induce cell cycle re-entry in postmitotic lens fiber cells of transgenic mice. Chen, Q., Liang, D., Yang, T., Leone, G., Overbeek, P.A. Dev. Neurosci. (2004) [Pubmed]
WikiGenes - Universities