e2f6 transcription factor


Summary: An E2F transcription factor that represses GENETIC TRANSCRIPTION required for CELL CYCLE entry and DNA synthesis. E2F6 recruits chromatin remodeling factors directly to target gene promoters and lacks the transactivation domain responsible for binding to the retinoblastoma family of tumor suppressors.

Top Publications

  1. Trimarchi J, Fairchild B, Verona R, Moberg K, Andon N, Lees J. E2F-6, a member of the E2F family that can behave as a transcriptional repressor. Proc Natl Acad Sci U S A. 1998;95:2850-5 pubmed
    ..Instead, it can act to repress the transcription of E2F responsive genes by countering the activity of the other E2F complexes via a pRB-, p107-, or p130-independent mechanism. ..
  2. Giangrande P, Zhu W, Schlisio S, Sun X, Mori S, Gaubatz S, et al. A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription. Genes Dev. 2004;18:2941-51 pubmed
  3. Yang W, Shu B, Zhu Y, Yang H. E2F6 inhibits cobalt chloride-mimetic hypoxia-induced apoptosis through E2F1. Mol Biol Cell. 2008;19:3691-700 pubmed publisher
    ..Together, these findings demonstrate a novel role of E2F6 in control of hypoxia-induced apoptosis through regulation of E2F1. ..
  4. Velasco G, Hube F, Rollin J, Neuillet D, Philippe C, Bouzinba Segard H, et al. Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues. Proc Natl Acad Sci U S A. 2010;107:9281-6 pubmed publisher
    ..Therefore, our results unraveled a coordinated regulation of genes involved in meiosis, through E2F6-dependant methylation and transcriptional silencing in somatic tissues. ..
  5. Gaubatz S, Wood J, Livingston D. Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6. Proc Natl Acad Sci U S A. 1998;95:9190-5 pubmed
    ..Taken together, these data suggest that E2F-6 can regulate a subset of E2F-dependent genes whose products are required for entry into the cell cycle but not for normal cell cycle progression. ..
  6. Attwooll C, Oddi S, Cartwright P, Prosperini E, Agger K, Steensgaard P, et al. A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. J Biol Chem. 2005;280:1199-208 pubmed
    ..Thus we have identified a novel E2F6-PcG complex (E2F6-EPC1) that interacts with EZH2 and may regulate genes required for cell cycle progression. ..
  7. Trimarchi J, Fairchild B, Wen J, Lees J. The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex. Proc Natl Acad Sci U S A. 2001;98:1519-24 pubmed
    ..These findings suggest that the biological properties of E2F6 are mediated through its ability to recruit the polycomb transcriptional repressor complex. ..
  8. Cartwright P, Muller H, Wagener C, Holm K, Helin K. E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription. Oncogene. 1998;17:611-23 pubmed
    ..Our data suggest that E2F-6 expression delays the exit from S-phase rather than inducing S-phase, which further emphasizes the functional difference between E2F-6 and the previously known E2F family members. ..
  9. Trimarchi J, Lees J. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002;3:11-20 pubmed
    ..What is the underlying molecular basis of this 'push-me-pull-you' regulation, and what are its biological consequences? ..

More Information


  1. Storre J, Elsässer H, Fuchs M, Ullmann D, Livingston D, Gaubatz S. Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6. EMBO Rep. 2002;3:695-700 pubmed
    ..The accumulated evidence suggests that, during development, E2F6 participates in the recruitment of polycomb proteins to specific target promoters...
  2. Yang W, Wang Z, Zhu Y, Yang H. E2F6 negatively regulates ultraviolet-induced apoptosis via modulation of BRCA1. Cell Death Differ. 2007;14:807-17 pubmed
    ..These findings provide the first demonstration of the important role for E2F6 in the control of apoptosis via targeting of BRCA1. ..
  3. 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. ..
  4. Morkel M, Wenkel J, Bannister A, Kouzarides T, Hagemeier C. An E2F-like repressor of transcription. Nature. 1997;390:567-8 pubmed
  5. Ogawa H, Ishiguro K, Gaubatz S, Livingston D, Nakatani Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 2002;296:1132-6 pubmed
    ..The E2F-6 complex preferentially occupies target promoters in G0 cells rather than in G1 cells. These data suggest that these chromatin modifiers contribute to silencing of E2F- and Myc-responsive genes in quiescent cells. ..
  6. Deshpande A, Akunowicz J, Reveles X, Patel B, Saria E, Gorlick R, et al. PHC3, a component of the hPRC-H complex, associates with E2F6 during G0 and is lost in osteosarcoma tumors. Oncogene. 2007;26:1714-22 pubmed
    ..Sequence analysis revealed that PHC3 was mutated in nine of 15 primary osteosarcoma tumors. These findings suggest that loss of PHC3 may favor tumorigenesis by potentially disrupting the ability of cells to remain in G(0). ..
  7. 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. ..
  8. Pestereli H, Erdogan O, Kaya R, Karaveli F. Lymphoepithelioma-like carcinoma of the breast. APMIS. 2002;110:447-50 pubmed
    ..This is the ninth case reported in the English literature and to the best of our knowledge the first one with lymph node metastasis. ..
  9. Pohlers M, Truss M, Frede U, Scholz A, Strehle M, Kuban R, et al. A role for E2F6 in the restriction of male-germ-cell-specific gene expression. Curr Biol. 2005;15:1051-7 pubmed
    ..Thus, E2F6 is essential for the long-term somatic silencing of certain male-germ-cell-specific genes, but it is dispensable for cell-cycle regulation. ..
  10. Lu Z, Luo R, Peng H, Huang M, Nishmoto A, Hunt K, et al. E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer. Oncogene. 2006;25:230-9 pubmed
    ..Taken together, our results suggest that E2F1, 4 and their complexes with HDAC play an important role in downregulating the expression of the tumor suppressor gene ARHI in breast cancer cells. ..
  11. Movassagh M, Bicknell K, Brooks G. Characterisation and regulation of E2F-6 and E2F-6b in the rat heart: a potential target for myocardial regeneration?. J Pharm Pharmacol. 2006;58:73-82 pubmed
    ..Taken together, abrogation of E2F-6 expression in neonatal cardiomyocytes leads to a significant decrease in their viability, consistent with the notion that E2F-6 might be required for maintaining normal myocyte growth. ..
  12. Bhatnagar N, Li X, Padi S, Zhang Q, Tang M, Guo B. Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Cell Death Dis. 2010;1:e105 pubmed publisher
    ..Thus, downregulation of miR-205 and miR-31 has an important role in apoptosis resistance in advanced prostate cancer. ..
  13. Bruhn S, Katzenellenbogen M, Gustafsson M, Krönke A, Sönnichsen B, Zhang H, et al. Combining gene expression microarray- and cluster analysis with sequence-based predictions to identify regulators of IL-13 in allergy. Cytokine. 2012;60:736-40 pubmed publisher
    ..In summary, our findings indicate an inhibitory role of E2F6 in the regulation of IL-13 and allergy. The analytical approach may be generally applicable to elucidate the complex regulatory patterns in Th2 cell polarization and allergy. ..
  14. Courel M, Friesenhahn L, Lees J. E2f6 and Bmi1 cooperate in axial skeletal development. Dev Dyn. 2008;237:1232-42 pubmed publisher
    ..These findings underscore the significance of the E2F6-Bmi1 interaction in vivo and suggest that the Hox and Ink4a-Arf loci are regulated by somewhat different mechanisms. ..
  15. Oberley M, Inman D, Farnham P. E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9. J Biol Chem. 2003;278:42466-76 pubmed
    ..In summary, we have identified 48 endogenous target genes of E2F6 and have shown that E2F6 can repress target promoters in a manner that does not require histone H3 methylation at lysine 9. ..
  16. Zhang W, Zeng Z, Zhou Y, Xiong W, Fan S, Xiao L, et al. Identification of aberrant cell cycle regulation in Epstein-Barr virus-associated nasopharyngeal carcinoma by cDNA microarray and gene set enrichment analysis. Acta Biochim Biophys Sin (Shanghai). 2009;41:414-28 pubmed
    ..These results suggested that cell cycle pathway was the most disregulated pathway in the EBV-associated NPC, and EBER-1 was closely associated with p16, CDK4, cyclin D1, and Rb.cyclin D1 could be the prognosis biomarker for NPC. ..
  17. Michal M. Meningeal nodules in teratoma of the testis. Virchows Arch. 2001;438:198-200 pubmed
  18. Berteaux N, Lottin S, Monte D, Pinte S, Quatannens B, Coll J, et al. H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J Biol Chem. 2005;280:29625-36 pubmed
    ..Based on these findings, we conclude that the H19 RNA is actively linked to E2F1 to promote cell cycle progression of breast cancer cells. This clearly supports the H19 oncogenic function in breast tumor genesis. ..
  19. Westendorp B, Major J, Nader M, Salih M, Leenen F, Tuana B. The E2F6 repressor activates gene expression in myocardium resulting in dilated cardiomyopathy. FASEB J. 2012;26:2569-79 pubmed publisher
    ..The data highlight an unprecedented role for the strict regulation of the E2F pathway in normal postnatal cardiac function. ..
  20. Leung J, Nevins J. E2F6 associates with BRG1 in transcriptional regulation. PLoS ONE. 2012;7:e47967 pubmed publisher
    ..Collectively, our studies suggest that E2F6 may recruit BRG1 in transcriptional regulation of genes important for G1/S phase transition of the cell cycle. ..
  21. Bertoli C, Klier S, MCGOWAN C, Wittenberg C, de Bruin R. Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription. Curr Biol. 2013;23:1629-37 pubmed publisher
    ..Given the critical role of replication stress in oncogene transformation, a detailed understanding of the molecular mechanisms involved in the checkpoint response will contribute to a better insight into cancer development. ..
  22. Sanchez Beato M, Sanchez E, Garcia J, Pérez Rosado A, Montoya M, Fraga M, et al. Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors. J Pathol. 2004;204:528-37 pubmed
    ..These results allow us to propose that the formation of transcription complexes with E2F6 may modify the functional status of PcG proteins in HSR cells. ..
  23. Lyons T, Salih M, Tuana B. Activating E2Fs mediate transcriptional regulation of human E2F6 repressor. Am J Physiol Cell Physiol. 2006;290:C189-99 pubmed
  24. Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 2008;68:2094-105 pubmed publisher
    ..Taken together, our results clearly show that miR-137 and miR-193a are tumor suppressor miRNAs epigenetically silenced during oral carcinogenesis. ..
  25. Kherrouche Z, De Launoit Y, Monte D. Human E2F6 is alternatively spliced to generate multiple protein isoforms. Biochem Biophys Res Commun. 2004;317:749-60 pubmed
    ..Regulatory elements necessary for basal transcription reside within a 134bp fragment as determined by transient transfection experiments. ..
  26. Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T. Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Mod Pathol. 2003;16:293-8 pubmed
    ..Glut1 as well as EMA are specific to perineurial cells, and CD34 seems to be immunoreactive to endoneurial fibroblasts. ..
  27. Wong C, Barnes L, Smith L, Popa C, Serewko Auret M, Saunders N. E2F6: a member of the E2F family that does not modulate squamous differentiation. Biochem Biophys Res Commun. 2004;324:497-503 pubmed
    ..These results demonstrate that E2F6 does not contain the domains required for modulation of squamous differentiation and imply isoform-specific functions for individual E2F family members. ..
  28. Kusek J, Greene R, Nugent P, Pisano M. Expression of the E2F family of transcription factors during murine development. Int J Dev Biol. 2000;44:267-77 pubmed
  29. de Jager S, Menges M, Bauer U, Murra J. Arabidopsis E2F1 binds a sequence present in the promoter of S-phase-regulated gene AtCDC6 and is a member of a multigene family with differential activities. Plant Mol Biol. 2001;47:555-68 pubmed
    ..AtE2F1 complexes bound to consensus E2F sequences and to the AtCDC6 promoter in vitro. We conclude that Arabidopsis contains a family of functionally distinct E2F genes, most probably involved in the G1-to-S phase progression. ..
  30. Vodovnik A. Capsular vascular proliferation associated with thyroid paraganglioma. Histopathology. 2002;41:273 pubmed
  31. Halaban R, Cheng E, Smicun Y, Germino J. Deregulated E2F transcriptional activity in autonomously growing melanoma cells. J Exp Med. 2000;191:1005-16 pubmed
  32. 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. ..
  33. Iezza G, Loh C, Lanman T, Yong W. June 2003: 33-year-old male with a frontal lobe mass. Brain Pathol. 2003;13:643-5 pubmed
    ..When MA is accompanied by a meningioma, it is generally not associated with clinical evidence of neurofibromatosis. It is important to distinguish MA from an invasive meningioma, because of its favorable prognosis after resection. ..
  34. Biernat W, Biernat S. Ductal sebaceoma (sebomatricoma). Pol J Pathol. 2000;51:55-7 pubmed
    ..The aspects of morphological distinction between sebomatricomas and poromas are presented with its clinical implications. ..
  35. Cook H, Burt M, Collett J, Whitehead M, Frampton C, Chapman B. Adult coeliac disease: prevalence and clinical significance. J Gastroenterol Hepatol. 2000;15:1032-6 pubmed
    ..2%. Unrecognized coeliac disease which was detected by population screening was three-fold more common than proven or suspected coeliac disease. Population screening may identify subjects who could benefit from treatment. ..
  36. Chang Y, Nakajima H, Illenye S, Lee Y, Honjo N, Makiyama T, et al. Caspase-dependent apoptosis by ectopic expression of E2F-4. Oncogene. 2000;19:4713-20 pubmed
    ..Our results suggest that expression of E2F-4 at elevated levels induces growth arrest and apoptosis of mammalian cells through a mechanism distinct from E2F-1 and DP-1. ..
  37. Canales Ibarra C, Magariños G, Olsoff Pagovich P, Ortiz Hidalgo C. Cutaneous sclerosing perineurioma of the digits: an uncommon soft-tissue neoplasm. Report of two cases with immunohistochemical analysis. J Cutan Pathol. 2003;30:577-81 pubmed
    ..We comment on the differential diagnosis of fibrous cutaneous lesions based on immunohistochemistry. ..
  38. Kikuchi J, Shimizu R, Wada T, Ando H, Nakamura M, Ozawa K, et al. E2F-6 suppresses growth-associated apoptosis of human hematopoietic progenitor cells by counteracting proapoptotic activity of E2F-1. Stem Cells. 2007;25:2439-47 pubmed
    ..These results suggest that E2F-6 provides a failsafe mechanism against loss of hematopoietic progenitor cells during proliferation. Disclosure of potential conflicts of interest is found at the end of this article. ..
  39. Dahme T, Wood J, Livingston D, Gaubatz S. Two different E2F6 proteins generated by alternative splicing and internal translation initiation. Eur J Biochem. 2002;269:5030-6 pubmed
    ..Our results suggest that translation of E2F6b is initiated by internal ribosome entry. We propose that regulated translation initiation can produce distinct E2F6 isoforms under different physiological conditions. ..
  40. La Thangue N. Transcription. Chromatin control--a place for E2F and Myc to meet. Science. 2002;296:1034-5 pubmed
  41. Kehoe S, Oka M, Hankowski K, Reichert N, Garcia S, McCarrey J, et al. A conserved E2F6-binding element in murine meiosis-specific gene promoters. Biol Reprod. 2008;79:921-30 pubmed publisher
    ..Further, E2F6 overexpression was capable of reducing their transcription. These findings indicate that E2F6 possesses a broad ability to bind to and regulate the meiosis-specific gene population. ..
  42. Kherrouche Z, De Launoit Y, Monte D. The NRF-1/alpha-PAL transcription factor regulates human E2F6 promoter activity. Biochem J. 2004;383:529-36 pubmed
    ..Our results indicate that NRF-1/alpha-PAL is implicated in the regulation of basal E2F6 gene expression. ..
  43. Leseva M, Santostefano K, Rosenbluth A, Hamazaki T, Terada N. E2f6-mediated repression of the meiotic Stag3 and Smc1? genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b. Epigenetics. 2013;8:873-84 pubmed publisher
    ..In addition, repression of Stag3 and Smc1? occurred in the absence of Dnmt3b. The data presented here suggest a primary role of PRC2 in E2f6-mediated gene silencing of the meiotic genes. ..
  44. Stielow C, Stielow B, Finkernagel F, Scharfe M, Jarek M, Suske G. SUMOylation of the polycomb group protein L3MBTL2 facilitates repression of its target genes. Nucleic Acids Res. 2014;42:3044-58 pubmed publisher
    ..Finally, we provide evidence that SUMOylation of L3MBTL2 facilitates repression of these PRC1.6-target genes by balancing the local H2Aub1 levels established by the ubiquitinating enzyme RING2 and the de-ubiquitinating PR-DUB complex. ..
  45. Kherrouche Z, Begue A, Stehelin D, Monte D. Molecular cloning and characterization of the mouse E2F6 gene. Biochem Biophys Res Commun. 2001;288:22-33 pubmed
    ..Isolation of the murine E2F6 gene is a step toward generation of genetically modified mouse models that will help to understand the functions of E2F6. ..
  46. Balarezo F, Muller R, Weiss R, Brown T, Knibbs D, Joshi V. Soft tissue perineuriomas in children: report of three cases and review of the literature [corrected]. Pediatr Dev Pathol. 2003;6:137-41 pubmed
    ..A review of the English language literature on perineuriomas in children is also included. ..
  47. Storre J, Schäfer A, Reichert N, Barbero J, Hauser S, Eilers M, et al. Silencing of the meiotic genes SMC1beta and STAG3 in somatic cells by E2F6. J Biol Chem. 2005;280:41380-6 pubmed
    ..Our findings suggest a molecular mechanism for the stable transcriptional silencing of meiotic genes in somatic cells by E2F6. ..
  48. Valery C, Sakka L, Poirier J. Problematic differential diagnosis between cerebellar liponeurocytoma and anaplastic oligodendroglioma. Br J Neurosurg. 2004;18:300-3 pubmed
    ..The second histological study revealed a liponeurocytoma, a benign tumour not requiring adjuvant therapy. This case emphasizes the importance of considering this diagnosis to prevent unnecessary irradiation of such rumours. ..
  49. Wang X, Choi J, Ding J, Yang L, Ngoka L, Lee E, et al. HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation. BMC Genomics. 2013;14:830 pubmed publisher
    ..Our results demonstrate that HOXC9 coordinates diverse cellular processes associated with differentiation by directly activating and repressing the transcription of distinct sets of genes. ..