e2f4 transcription factor


Summary: An E2F transcription factor that represses GENETIC TRANSCRIPTION required for CELL CYCLE entry and DNA synthesis. E2F4 recruits chromatin remodeling factors indirectly to target gene PROMOTER REGIONS through RETINOBLASTOMA LIKE PROTEIN P130 and RETINOBLASTOMA LIKE PROTEIN P107.

Top Publications

  1. Pippa R, Espinosa L, Gundem G, GarcĂ­a Escudero R, Dominguez A, Orlando S, et al. p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes. Oncogene. 2012;31:4207-20 pubmed publisher
    ..Thus, this new function of p27 as a transcriptional repressor could have a role in the major aggressiveness of tumors with low levels of p27. ..
  2. Muller H, Moroni M, Vigo E, Petersen B, Bartek J, Helin K. Induction of S-phase entry by E2F transcription factors depends on their nuclear localization. Mol Cell Biol. 1997;17:5508-20 pubmed
  3. Rempel R, Saenz Robles M, Storms R, Morham S, Ishida S, Engel A, et al. Loss of E2F4 activity leads to abnormal development of multiple cellular lineages. Mol Cell. 2000;6:293-306 pubmed
    ..These observations suggest a critical role for E2F4 activity in controlling the maturation of cells in a number of tissues. ..
  4. Yochum G, Cleland R, McWeeney S, Goodman R. An antisense transcript induced by Wnt/beta-catenin signaling decreases E2F4. J Biol Chem. 2007;282:871-8 pubmed
    ..We propose that Wnt/beta-catenin signaling may contribute to colorectal carcinogenesis by reducing the level of the E2F4 cell cycle repressor via an antisense mechanism. ..
  5. Dagnino L, Fry C, Bartley S, Farnham P, Gallie B, Phillips R. Expression patterns of the E2F family of transcription factors during mouse nervous system development. Mech Dev. 1997;66:13-25 pubmed
    ..We conclude that individual E2F forms are differentially regulated during the development of distinct tissues, and especially during neuronal development. ..
  6. Mady H, Hasso S, Melhem M. Expression of E2F-4 gene in colorectal adenocarcinoma and corresponding covering mucosa: an immunohistochemistry, image analysis, and immunoblot study. Appl Immunohistochem Mol Morphol. 2002;10:225-30 pubmed
    ..These data suggest that E2F-4 gene overexpression plays a role in the development of colorectal tumors and appears to play a role in suppressing apoptosis. ..
  7. Xiao Z, Ginsberg D, Ewen M, Livingston D. Regulation of the retinoblastoma protein-related protein p107 by G1 cyclin-associated kinases. Proc Natl Acad Sci U S A. 1996;93:4633-7 pubmed
    ..In addition, E2F-4 binds selectively to hypophosphorylated p107, and G1 cyclin-dependent p107 phosphorylation leads to the dissociation of p107-E2F-4 complexes as well as inactivation of p107 G1 blocking function. ..
  8. Lee E, Cam H, Ziebold U, Rayman J, Lees J, Dynlacht B. E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer Cell. 2002;2:463-72 pubmed
    ..We also detect these novel E2F complexes in pRB-deficient cells, suggesting that they play a significant role in the regulation of tumorigenesis in vivo. ..
  9. Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson S, Velmurugan S, et al. Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell. 2007;26:539-51 pubmed
    ..This work reveals an evolutionarily conserved multisubunit protein complex that contains p130 and E2F4, but not pRB, and mediates the repression of cell cycle-dependent genes in quiescence. ..

More Information


  1. Gaubatz S, Lees J, Lindeman G, Livingston D. E2F4 is exported from the nucleus in a CRM1-dependent manner. Mol Cell Biol. 2001;21:1384-92 pubmed
    ..Taken together, these data suggest that nuclear export contributes to the regulation of E2F4 function, including its ability to regulate exit from G1 in association with a suitable pocket protein. ..
  2. van Oevelen C, Wang J, Asp P, Yan Q, Kaelin W, Kluger Y, et al. A role for mammalian Sin3 in permanent gene silencing. Mol Cell. 2008;32:359-70 pubmed publisher
  3. Kinross K, Clark A, Iazzolino R, Humbert P. E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation. Blood. 2006;108:886-95 pubmed
    ..We conclude that the macrocytic anemia of E2f4(-/-) mice results primarily from impaired cellular proliferation and that the major role of E2f4 in fetal erythropoiesis is to promote cell cycle progression and cellular proliferation. ..
  4. Maiti B, Li J, de Bruin A, Gordon F, Timmers C, Opavsky R, et al. Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem. 2005;280:18211-20 pubmed
    ..These observations, together with the fact that E2F7 and E2F8 can homodimerize and are expressed in the same adult tissues, suggest that they may have overlapping and perhaps synergistic roles in the control of cellular proliferation. ..
  5. Schwemmle S, Pfeifer G. Genomic structure and mutation screening of the E2F4 gene in human tumors. Int J Cancer. 2000;86:672-7 pubmed
    ..Our data suggest that a direct involvement of E2F4 in tumorigenesis is unlikely, although increased E2F4 expression may be associated with human cancer. ..
  6. Chen C, Kang Y, Siegel P, Massague J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell. 2002;110:19-32 pubmed
    ..Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners. ..
  7. Cam H, Balciunaite E, Blais A, Spektor A, Scarpulla R, Young R, et al. A common set of gene regulatory networks links metabolism and growth inhibition. Mol Cell. 2004;16:399-411 pubmed
    ..Our studies provide insights into E2F regulatory circuitry, suggest how factor occupancy can predict the expression signature of a given target gene, and reveal pathways deregulated in human tumors. ..
  8. Rayman J, Takahashi Y, Indjeian V, Dannenberg J, Catchpole S, Watson R, et al. E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev. 2002;16:933-47 pubmed
  9. Dagnino L, Fry C, Bartley S, Farnham P, Gallie B, Phillips R. Expression patterns of the E2F family of transcription factors during murine epithelial development. Cell Growth Differ. 1997;8:553-63 pubmed
    ..Thus, selective regulation of E2F forms occurs during murine epithelial development, irrespective of the ectodermal or endodermal origin of such epithelia. ..
  10. Ferreira R, Magnaghi Jaulin L, Robin P, Harel Bellan A, Trouche D. The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. Proc Natl Acad Sci U S A. 1998;95:10493-8 pubmed
    ..Taken together, our data suggest that all members of the E2F family are regulated in early G1 by similar complexes, containing a pocket protein and the histone deacetylase HDAC1. ..
  11. van Amerongen M, Diehl F, Novoyatleva T, Patra C, Engel F. E2F4 is required for cardiomyocyte proliferation. Cardiovasc Res. 2010;86:92-102 pubmed publisher
    ..Moreover, chromatin immunoprecipitation showed that E2F4 binds to centromeric alpha-satellite DNA during mitosis. Our data indicate that E2F4 is required for cardiomyocyte proliferation and suggest a function for E2F4 in mitosis. ..
  12. Balciunaite E, Spektor A, Lents N, Cam H, te Riele H, Scime A, et al. Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol Cell Biol. 2005;25:8166-78 pubmed
  13. DeschĂȘnes C, Alvarez L, Lizotte M, Vezina A, Rivard N. The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation. J Cell Physiol. 2004;199:262-73 pubmed
  14. Roman A. The human papillomavirus E7 protein shines a spotlight on the pRB family member, p130. Cell Cycle. 2006;5:567-8 pubmed
  15. Conboy C, Spyrou C, Thorne N, Wade E, Barbosa Morais N, Wilson M, et al. Cell cycle genes are the evolutionarily conserved targets of the E2F4 transcription factor. PLoS ONE. 2007;2:e1061 pubmed
    ..Thus, the regulatory mechanisms maintaining quiescence are robust even to complete loss of conserved transcription factor binding events. ..
  16. Takahashi Y, Rayman J, Dynlacht B. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 2000;14:804-16 pubmed
    ..These findings suggest that repression and activation of E2F-responsive genes may occur through distinct E2F heterodimers that direct the sequential recruitment of enzymes able to deacetylate and then acetylate core histones. ..
  17. Danielian P, Bender Kim C, Caron A, Vasile E, Bronson R, Lees J. E2f4 is required for normal development of the airway epithelium. Dev Biol. 2007;305:564-76 pubmed
    ..Importantly, the combination of no ciliated cells and excess mucous cells can account for the chronic rhinitis and increased susceptibility to opportunistic infections that causes the postnatal lethality of E2f4 mutant mice. ..
  18. Crosby M, Almasan A. Opposing roles of E2Fs in cell proliferation and death. Cancer Biol Ther. 2004;3:1208-11 pubmed
    ..The balance between the activities of these two proteins in tumor cells is of great interest. Directed control of E2F1 and E2F4 action may lead to better diagnosis of disease and improved therapeutic modalities. ..
  19. Yang J, Song K, Krebs T, Jackson M, Danielpour D. Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene. 2008;27:5326-38 pubmed publisher
    ..We propose a novel TGF-beta/Rb/survivin axis with a putative role in the functional switch of TGF-beta from tumor suppressor to tumor promoter. ..
  20. Gill R, Hamel P. Subcellular compartmentalization of E2F family members is required for maintenance of the postmitotic state in terminally differentiated muscle. J Cell Biol. 2000;148:1187-201 pubmed
    ..These data demonstrate that regulation of the subcellular compartmentalization of E2F-family members is required to maintain nuclei in a quiescent state in terminally differentiated cells. ..
  21. Humbert P, Rogers C, Ganiatsas S, Landsberg R, Trimarchi J, Dandapani S, et al. E2F4 is essential for normal erythrocyte maturation and neonatal viability. Mol Cell. 2000;6:281-91 pubmed
    ..This suggests that E2F4 makes a major contribution to the control of erythrocyte development by the pRB tumor suppressor. ..
  22. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park C, et al. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell. 2001;8:105-13 pubmed
    ..From this data, we propose that the induction of specific E2F activities is an essential component in the Myc pathways that control cell proliferation and cell fate decisions. ..
  23. Scime A, Li L, Ciavarra G, Whyte P. Cyclin D1/cdk4 can interact with E2F4/DP1 and disrupts its DNA-binding capacity. J Cell Physiol. 2008;214:568-81 pubmed
    ..These data support a model in which E2F4 DNA binding is abolished during mid-G(1) at the same time when E2F interactions with pRb-related proteins are disrupted by cyclin D1/cdk4. ..
  24. Rabinovich A, Jin V, Rabinovich R, Xu X, Farnham P. E2F in vivo binding specificity: comparison of consensus versus nonconsensus binding sites. Genome Res. 2008;18:1763-77 pubmed publisher
  25. Caretti G, Salsi V, Vecchi C, Imbriano C, Mantovani R. Dynamic recruitment of NF-Y and histone acetyltransferases on cell-cycle promoters. J Biol Chem. 2003;278:30435-40 pubmed
    ..These data indicate that following the release of E2Fs/HDACs, a hierarchy of PCAF-NF-Y-p300 interactions and H3-H4 acetylations are required for activation of cell-cycle promoters. ..
  26. Popov B, Chang L, Serikov V. Cell cycle-related transformation of the E2F4-p130 repressor complex. Biochem Biophys Res Commun. 2005;336:762-9 pubmed
    ..In contrast to T98G cells, transformation of the p130 containing cyc/cdk-pp-E2F4 complex into the p130-pp-E2F4 repressor does not occur in HeLa cells under growth restriction conditions. ..
  27. Xu X, Bieda M, Jin V, Rabinovich A, Oberley M, Green R, et al. A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members. Genome Res. 2007;17:1550-61 pubmed
    ..Our results support the concept of functional redundancy in the E2F family and suggest that E2F6 is not critical for histone methylation. ..
  28. Sardet C, Vidal M, Cobrinik D, Geng Y, Onufryk C, Chen A, et al. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proc Natl Acad Sci U S A. 1995;92:2403-7 pubmed
    ..These findings suggest that E2F-4 and E2F-5 may contribute to the regulation of early G1 events including the G0/G1 transition. ..
  29. Ginsberg D, Vairo G, Chittenden T, Xiao Z, Xu G, Wydner K, et al. E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes Dev. 1994;8:2665-79 pubmed
    ..p107 binding not only can be linked to the regulation of E2F-4 transcriptional activity, but also to suppression of the ability of E2F-4 to transform an immortalized rodent cell line. ..
  30. Karlseder J, Rotheneder H, Wintersberger E. Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol Cell Biol. 1996;16:1659-67 pubmed
    ..Our data are in line with the hypothesis that E2F functions as a growth- and cell cycle regulated tethering factor between Sp1 and the basic transcription machinery. ..
  31. Blahnik K, Dou L, O Geen H, McPhillips T, Xu X, Cao A, et al. Sole-Search: an integrated analysis program for peak detection and functional annotation using ChIP-seq data. Nucleic Acids Res. 2010;38:e13 pubmed publisher
    ..We demonstrate the utility of our software by collecting, analyzing and comparing ChIP-seq data for six different human transcription factors/cell line combinations. ..
  32. Ikeda M, Jakoi L, Nevins J. A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation. Proc Natl Acad Sci U S A. 1996;93:3215-20 pubmed
    ..These results suggest that the specific ability of Rb protein to interact with each E2F species, dependent on concentration of active Rb relative to accumulation of E2F, may be critical in cell-growth decisions. ..
  33. Magae J, Wu C, Illenye S, Harlow E, Heintz N. Nuclear localization of DP and E2F transcription factors by heterodimeric partners and retinoblastoma protein family members. J Cell Sci. 1996;109 ( Pt 7):1717-26 pubmed
    ..These results indicate that DP proteins preferentially associate with specific E2F partners, and suggest that the ability of specific E2F/DP heterodimers to localize in the nucleus contributes to the regulation of E2F activity. ..
  34. Hoshikawa Y, Mori A, Amimoto K, Iwabe K, Hatakeyama M. Control of retinoblastoma protein-independent hematopoietic cell cycle by the pRB-related p130. Proc Natl Acad Sci U S A. 1998;95:8574-9 pubmed
    ..Our results indicate the existence of a non-pRB-based cell cycle whose operation depends primarily on the interplay between p130 and E2F-4 in certain hematopoietic cells. ..
  35. Lindeman G, Gaubatz S, Livingston D, Ginsberg D. The subcellular localization of E2F-4 is cell-cycle dependent. Proc Natl Acad Sci U S A. 1997;94:5095-100 pubmed
    ..Thus, the subcellular location of E2F-4 is regulated in a cell cycle-dependent manner, providing another potential mechanism for its functional regulation. ..
  36. Verona R, Moberg K, Estes S, Starz M, Vernon J, Lees J. E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol. 1997;17:7268-82 pubmed
    ..How the differential subcellular localization of pRB, p107, and p130 contributes to their different biological properties is also discussed. ..
  37. Beijersbergen R, Carlee L, Kerkhoven R, Bernards R. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes Dev. 1995;9:1340-53 pubmed
    ..A p107-induced cell cycle block can be released by cyclin D1/cdk4 but not by cyclin E/cdk2. These data indicate that the activity of p107 is regulated by phosphorylation through D-type cyclins. ..
  38. Garneau H, Paquin M, Carrier J, Rivard N. E2F4 expression is required for cell cycle progression of normal intestinal crypt cells and colorectal cancer cells. J Cell Physiol. 2009;221:350-8 pubmed publisher
    ..These results indicate that nuclear E2F4 may be determinant in the promotion of proliferation of human intestinal epithelial crypt cells and colorectal cancer cells. ..
  39. Parisi T, Bronson R, Lees J. Inhibition of pituitary tumors in Rb mutant chimeras through E2f4 loss reveals a key suppressive role for the pRB/E2F pathway in urothelium and ganglionic carcinogenesis. Oncogene. 2009;28:500-8 pubmed publisher
    ..Moreover, a subset of the Rb(-/-);E2f4(-/-) chimeras developed either low- or high-grade carcinomas in the urothelium transitional epithelium supporting a key role for Rb in bladder cancer. ..
  40. Strom D, Cleveland J, Chellappan S, Nip J, Hiebert S. E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Cell Growth Differ. 1998;9:59-69 pubmed
    ..Therefore, E2F-1, but not E2F-3, can temporally replace the requirement for growth factors to promote cell cycle progression, and in terminally differentiating cells, this leads to a block in differentiation and induction of apoptosis. ..
  41. Zheng N, Fraenkel E, Pabo C, Pavletich N. Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev. 1999;13:666-74 pubmed
    ..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. ..
  42. Wang D, Russell J, Johnson D. E2F4 and E2F1 have similar proliferative properties but different apoptotic and oncogenic properties in vivo. Mol Cell Biol. 2000;20:3417-24 pubmed
    ..These findings demonstrate that while the effects of E2F1 and E2F4 on cell proliferation in vivo are similar, their apoptotic and oncogenic properties are quite different. ..
  43. Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young R, et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 2002;16:245-56 pubmed
    ..1200 genes expressed during cell cycle entry, we found that the promoters of 127 were bound by the E2F4 transcription factor in primary fibroblasts. A subset of these targets was also bound by E2F1...
  44. Furukawa Y, Iwase S, Kikuchi J, Nakamura M, Yamada H, Matsuda M. Transcriptional repression of the E2F-1 gene by interferon-alpha is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes. Oncogene. 1999;18:2003-14 pubmed
    ..Our findings indicate that E2F-4 is a critical regulator of E2F-1, which offer an excellent paradigm for understanding functional diversity within the E2F family. ..
  45. Moberg K, Starz M, Lees J. E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol Cell Biol. 1996;16:1436-49 pubmed
    ..Despite this, a considerable amount of E2F-4 exists as free E2F. In G1 cells, this accounts for almost all of the free activity. Once the cells enter S phase, free E2F is composed of an equal mixture of E2F-4 and E2F-1. ..
  46. Gaubatz S, Lindeman G, Ishida S, Jakoi L, Nevins J, Livingston D, et al. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell. 2000;6:729-35 pubmed
    ..However, they failed to arrest in G1 in response to p16INK4a. Thus, E2F4 and E2F5 are dispensable for cell cycle progression but necessary for pocket protein-mediated G1 arrest of cycling cells. ..
  47. Richon V, Venta Perez G. Changes in E2F DNA-binding activity during induced erythroid differentiation. Cell Growth Differ. 1996;7:31-42 pubmed
    ..Thus, HMBA causes a selective loss in the free E2F DNA-binding complex, an increase in p107 protein, and an increase in a form of E2F protein during MEL cell differentiation. ..
  48. Dhillon N, Mudryj M. Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest. Oncogene. 2002;21:4626-34 pubmed
    ..Moreover, these results provide one explanation of why some cells that express the estrogen receptor may be unresponsive to antiestrogens. ..
  49. Plesca D, Crosby M, Gupta D, Almasan A. E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell Cycle. 2007;6:1147-52 pubmed
    ..Here we review these recent findings and discuss the mechanisms of G2 phase checkpoint activation and maintenance with a particular focus on E2F4. ..
  50. Goldfine A, Crunkhorn S, Costello M, Gami H, Landaker E, Niinobe M, et al. Necdin and E2F4 are modulated by rosiglitazone therapy in diabetic human adipose and muscle tissue. Diabetes. 2006;55:640-50 pubmed
    ..These data suggest that changes in necdin and E2F4 expression after rosiglitazone exposure in humans are associated with altered adipocyte differentiation and may contribute to improved insulin sensitivity in humans treated with TZDs. ..
  51. Lam E, Glassford J, van der Sman J, Banerji L, Pizzey A, Shaun N, et al. Modulation of E2F activity in primary mouse B cells following stimulation via surface IgM and CD40 receptors. Eur J Immunol. 1999;29:3380-9 pubmed
    ..These results therefore indicate that the pRB/E2F pathway integrates proliferative signals emanating from the sIgM and CD40 receptors. ..
  52. Yanagino T, Yuasa K, Nagahama M, Matsuda Y, Tsuji A. Transcriptional regulation of fibrillin-2 gene by E2F family members in chondrocyte differentiation. J Cell Biochem. 2009;106:580-8 pubmed publisher
    ..These results indicated that coordinated expression of the E2F family is critical for the transcriptional regulation of fibrillin-2 during chondrogenesis. ..
  53. Lo K, Bauchmann M, Baumann A, Donahue C, Thiede M, Hayes L, et al. Genome-wide profiling of H3K56 acetylation and transcription factor binding sites in human adipocytes. PLoS ONE. 2011;6:e19778 pubmed publisher
    ..This is the first genome-wide profile of H3K56 acetylation, E2F4, C/EBP? and HSF-1 binding in human adipocytes, and will serve as an important resource for better understanding adipocyte transcriptional regulation. ..