Schematic representation of the E2F transcription factor subgroups, their physiological roles and specific binding partners. (A) The E2F family is divided into at least four subgroups defined by their regulation by pocket proteins and chromatin modifiers, and by their physiological function (i.e. activation or repression). See text for details. ‘DP' presents DP1 or DP2, ‘chromatin modifiers' refer to chromatin-modifying activities binding to the pRB family members, such as HDAC, Suv39H, BRG1 or HPC2. Recent results from our laboratory have shown that also E2F7 recruits repressors to E2F-dependent promoters (Di Stefano and Helin, unpublished results). (B) Specificity among the E2Fs through protein–protein interactions. TopBP1 and GABPγ1 are specific binding partners of E2F1, while TFE3 binds only to E2F3, and RYBP and YY1 bind only to E2Fs 2 and 3.

Models for the mechanism of regulation of E2F-dependent promoters. (A) ‘Active repression model': repressing E2Fs recruit chromatin modifiers to E2F-dependent promoters; thus, this repression must be relieved (chromatin remodelling) before promoters can be activated. In addition, the repressing E2Fs physically prevent binding of the E2F target promoter by the activating E2Fs. In this model, and in the models shown in panels B and C, pRB represents the pRB family members. (B) ‘Passive repression model': pRB prevents E2F promoter activation by binding to the transactivation domains of the E2Fs. This binding may also prevent the recruitment of essential co-activators to the promoter. Repression is relieved by phosphorylation of pRB and its concomitant dissociation from E2Fs, freeing the transactivation domain for activity. (C) ‘Competition model': the activating and repressing E2Fs compete for binding to the E2F DNA-binding site. This model also includes the recruitment of chromatin modifiers by pRB family members.

Models for the regulation of gene expression by the E2F transcription factors. (A) Classical model for the regulation of E2F-dependent promoters by the E2Fs. This model is based on the original observations of E2F-binding partners, localisation studies and promoter affinities. See text for details of this model. (B) The ‘ChIP model' for E2F regulation of target promoters. Using ChIP assays, pRB has not been found to be associated with promoters containing the E2F consensus site during normal cell cycle progression. Thus, the ChIP model predicts that p130- and p107-, but not pRB-containing complexes, regulate E2F-dependent transcription in proliferating cells, whereas pRB-containing complexes may have a role in regulating E2F-dependent promoters in cells exiting the cell cycle (senescence/terminal differentiation). In addition to HDAC, chromatin modifiers such as Suv39H, BRG1 and HPC2 have also been shown to associate with pRB. (C) The ‘combined model' for E2F regulation of target promoters. This model combines those shown in panels A and B, and postulates that pRB, in association with E2F-DP, also regulates the expression of thus far unidentified E2F target genes (‘non-ChIP targets'), which are important for the regulation of the cell cycle. This model is supported by the observation that inactivation of pRb in mouse cells lead to deregulation of the cell cycle.