Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation

The transcription factor E2F-1 is important in the control of cell prolifer ation. Its activity must be tightly regulated in a cell-cycle-dependent man ner to enable programs of gene expression to be coupled closely with cell-c ycle position. Here we show that, following its accumulation in the late G1 phase of the cell cycle, E2F-1 is rapidly degraded in S/G2 phase. This eve nt is linked to a specific interaction of E2F-1 with the F-box-containing p rotein p45(SKP2), which is the cell-cycle-regulated component of the ubiqui tin-protein ligase SCFSKP2 that recognizes substrates for this ligase. Disr uption of the interaction between E2F-1 and p45(SKP2) results in a reductio n in ubiquitination of E2F-1 and the stabilization and accumulation of tran scriptionally active E2F-1 protein. These results indicate that an SCFSKP2- dependent ubiquitination pathway may be involved in the downregulation of E 2F-1 activity in the S/G2 phase of the cell cycle, and suggest a link betwe en SCFSKP2 and cell-cycle-dependent gene control.