Cloning and Characterization of Mouse E2F8, a Novel Mammalian E2F Family Member Capable of Blocking Cellular Proliferation

Abstract

The E2F transcription factor family plays a crucial and well established role in cell cycle progression. Deregulation of E2F activities in vivo leads to developmental defects and cancer. Based on current evidence in the field, mammalian E2Fs can be functionally categorized into either transcriptional activators (E2F1, E2F2, and E2F3a) or repressors (E2F3b, E2F4, E2F5, E2F6, and E2F7). We have identified a novel E2F family member, E2F8, which is conserved in mice and humans and has its counterpart in Arabidopsis thaliana (E2Ls). Interestingly, E2F7 and E2F8 share unique structural features that distinguish them from other mammalian E2F repressor members, including the presence of two distinct DNA-binding domains and the absence of DP-dimerization, retinoblastoma-binding, and transcriptional activation domains. Similar to E2F7, overexpression of E2F8 significantly slows down the proliferation of primary mouse embryonic fibroblasts. 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.

Retinoblastoma family genes

“…Consistent with these structural features, this subgroup of E2Fs functions mainly as repressors of E2F target gene expression, and they translocate into the nucleus when in complex with the Rb family of proteins during the G0/G1 phases of the cell cycle (Muller et al, 1997;Verona et al, 1997). E2Fs 6-8, representing the remaining two subgroups, also function as transcriptional repressors (Trimarchi et al, 1998(Trimarchi et al, , 2001de Bruin et al, 2003a;Di Stefano et al, 2003;Attwooll et al, 2004b;Maiti et al, 2005). However, in contrast to E2Fs 1-5, these E2F proteins do not have the Rb-binding sequence at the C-terminus, and therefore their function and regulation are independent of the Rb family of proteins.…”

E2f6 and Bmi1 cooperate in axial skeletal development

“…E2f6-8 are more distantly related members of the E2F family. 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).…”

E2F6 negatively regulates ultraviolet-induced apoptosis via modulation of BRCA1

“…The human E2F family of transcription factors has eight known family members (E2F1-8) 2,[5][6][7] and two dimeric partners (DRTF1-polypeptide-1 and DRTF1-polypeptide-2), the latter of which forms heterodimers to generate functional E2F complexes. 8,9 E2F members possess highly conserved DNA binding and heterodimerization domains, with the exception of E2F7 and E2F8.…”

“…8,9 E2F members possess highly conserved DNA binding and heterodimerization domains, with the exception of E2F7 and E2F8. 6,7 The E2F family can be functionally categorized into either transcriptional 'activators' (E2F1-2, E2F3a) or 'repressors' (E2F3b, E2F4-8). 2,10 Activators E2F1, E2F2, and E2F3a are negatively regulated by interaction with pRb, a tumor suppressor protein.…”

“…2,10 E2F7 and E2F8, the most recently identified ones, can function as repressors, independent of DP interaction, to negatively influence cellular proliferation. 6,7 E2F6 lacks the transactivation and pocket protein (pRb, p107, and p130) binding domains found in other E2Fs, and can repress the transcription of known E2F-responsive genes. 5 It has also been shown that its carboxyl terminus has repression activity.…”