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Fig. 2. pRB- and E2F-family members are involved in two distinct types of regulation. The conventional view of E2F is as a cell-cycle oscillator in which complexes of pRB- and E2F-family members provide transient repression that is readily reversed each cell cycle. E2F-binding sites are occupied by repressor E2Fs in G0/G1 and these are replaced by activator E2Fs in late-G1/early-S phase. This transition is driven by CDKs and probably involves the phosphorylation of RB-family proteins and the disruption of repressor complexes. E2F-4 can be found at E2F-regulated promoters in S phase, but it is unclear whether it acts as an activator. In addition to transient repression of cell-cycle genes, pRB-family members are involved in the stable repression of transcription. Stable repression by E2F-RB complexes has been observed in actively proliferating cells, independent of cell-cycle position, and in cells that have withdrawn from the cell cycle. The mechanisms involved in the initiation, maintenance and, potentially, the reversal of stable RB/E2F-mediated repression are largely unknown.
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