Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6

Abstract

E2F transcription factors play an important role in the regulation of cell cycle progression. We report here the cloning and characterization of an additional member of this family, E2F-6. E2F-6 lacks pocket protein binding and transactivation domains, and it is a potent transcriptional repressor that contains a modular repression domain at its carboxyl terminus. Overproduction of E2F-6 had no specific effect on cell cycle progression in asynchronously growing Saos2 and NIH 3T3 cells, but it inhibited entry into S phase of NIH 3T3 cells stimulated to exit G0. 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.

E2F6 negatively regulates ultraviolet-induced apoptosis via modulation of BRCA1

“…The plasmids, pcDNA3-HA-E2F6 (E2F6 cDNA constructs) and pcDNA3-HA-E2F6DC (D220-281, lacking the repression domain of E2F6), were provided by Professor David M Livingston (Harvard Medical School, Boston). 12 The BRCA1 C-terminal fragments KE in pcDNA4 (BRCA1-KE) were obtained from Dr. QM Zhan. 21 To generate the EGFP-containing E2F6wt and E2F6DC expression vectors, an EcoR I-Xab I CMV-EGFP-containing fragment from pAdtrack-CMV (Qbiogene) was subcloned into pcDNA3-HA-E2F6 and pcDNA3-HA-E2F6DC, respectively.…”

“…5 It has also been shown that its carboxyl terminus has repression activity. 12 Overexpression of E2F6 leads to accumulation of cells in the S-phase and delays re-entry into the cell cycle in quiescent cells. 13 More recently, E2F6 has been suggested to repress transcription of BRCA1, CTIP, ART27, HP-1a, and RBAP48 genes (which encode functions involved in tumor suppression and maintenance of chromatin structure) via its repression of the target promoter.…”

E2f6 and Bmi1 cooperate in axial skeletal development

“…In particular, they lack the domain required for pocket protein-binding and are therefore not susceptible to pocket protein regulation (Morkel et al, 1997;Trimarchi et al, 1998Trimarchi et al, , 2001Cartwright et al, 1998;Gaubatz et al, 1998;de Bruin et al, 2003;Logan et al, 2004;Maiti et al, 2005). E2F6 binds DNA as a heterodimer with DP, in a similar manner to E2F1-5, but due to the absence of a transactivation domain it does not activate transcription (Morkel et al, 1997;Cartwright et al, 1998;Gaubatz et al, 1998;Trimarchi et al, 1998). Early studies showed that overexpressed E2F6 can repress classic E2F-responsive genes, at least in part, by binding to E2F-responsive promoters and blocking access to other activating E2Fs (Morkel et al, 1997;Gaubatz et al, 1998;Trimarchi et al, 1998).…”

“…E2F6 binds DNA as a heterodimer with DP, in a similar manner to E2F1-5, but due to the absence of a transactivation domain it does not activate transcription (Morkel et al, 1997;Cartwright et al, 1998;Gaubatz et al, 1998;Trimarchi et al, 1998). Early studies showed that overexpressed E2F6 can repress classic E2F-responsive genes, at least in part, by binding to E2F-responsive promoters and blocking access to other activating E2Fs (Morkel et al, 1997;Gaubatz et al, 1998;Trimarchi et al, 1998). Subsequently, E2F6 was shown to exist in complexes that contain both chromatin remodeling enzymes and members of the mammalian Polycomb Group (PcG), including Bmi1, Ring1, and RYBP (Trimarchi et al, 2001;Ogawa et al, 2002;Attwooll et al, 2004).…”

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

“…Downregulation of expression of the transcription factor and key cell cycle regulator, E2F, is an early event in normal squamous di erentiation (Saunders et al, 1993b). There are currently six known members of the E2F family in humans, E2F-1 to E2F-6 (Kaelin et al, 1992;Shan et al, 1992;Helin et al, 1992;Lees et al, 1993;Ivey-Hoyle et al, 1993;Beijersbergen et al, 1994;Ginsberg et al, 1994;Itoh et al, 1995;Buck et al, 1995;Gaubatz et al, 1998;Trimarchi et al, 1998;Cartwright et al, 1998), which associate with one of two dimerization partners (DP1 and DP2) (Girling et al, 1993;Rogers et al, 1996) to increase the activity of E2F bound to the promoter region of E2F responsive genes. E2F-1 is the best characterized of the family, with evidence implicating it as a key regulator of G1/S phase traverse (Johnson and Schneider-Broussard, 1998;Yee et al, 1998).…”