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First published online May 4, 2004
doi: 10.1242/10.1242/jcs.01227

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Molecular mechanisms of E2F-dependent activation and pRB-mediated repression

Massachusetts General Hospital Cancer Center, Bldg 149, 13th Street, Charlestown, MA 02129, USA

View larger version (13K): [in a new window]   Fig. 1. Structure of E2F-family members. E2F-1–E2F-6 contain a DNA-binding domain (DBD) and a DP-dimerization domain that includes two conserved motifs: a leucine repeat sequence (LZ) and the marked box (MB). Unlike other E2Fs, E2F-7 has two distinct DBDs and does not require DP to bind to DNA (de Bruin et al., 2003; Di Stefano et al., 2003). E2F-1–E2F-5 contain a conserved C-terminal motif that mediates association with pRB-family members (RB).

View larger version (19K): [in a new window]   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complexes has been observed in actively proliferating cells, independent of cell-cycle position, and in cells that have withdrawn from the cell cycle.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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