Abstract
The transcription factor E2F-1 is important in the control of cell proliferation. Its activity must be tightly regulated in a cell-cycle-dependent manner to enable programs of gene expression to be coupled closely with cell-cycle 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 event is linked to a specific interaction of E2F-1 with the F-box-containing protein p45SKP2, which is the cell-cycle-regulated component of the ubiquitin–protein ligase SCFSKP2 that recognizes substrates for this ligase. Disruption of the interaction between E2F-1 and p45SKP2 results in a reduction in ubiquitination of E2F-1 and the stabilization and accumulation of transcriptionally active E2F-1 protein. These results indicate that an SCFSKP2-dependent ubiquitination pathway may be involved in the downregulation of E2F-1 activity in the S/G2 phase of the cell cycle, and suggest a link between SCFSKP2 and cell-cycle-dependent gene control.
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Acknowledgements
We thank the members of our laboratory for many helpful discussions; H. Angliker for sequencing and P. Müller for synthesis of oligonucleotides; D. Beach for p45SKP2 and p19SKP1 cDNAs and for the GST–p45SKP2 baculovirus; A. Pause and R. Klausner for HA-tagged CUL-1 plasmid; D. Bohmann for the HA–ubiquitin plasmid; E. Harlow for pCMV–CDC2; and B. Amati, R. Eckner, P. Caroni, N. Hynes, P. Matthias and members of our laboratory for careful reading of the manuscript. W. K. is a START fellow and is supported by the Swiss National Science Foundation.
Correspondence and requests for materials should be addressed to W. K.
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Marti, A., Wirbelauer, C., Scheffner, M. et al. Interaction between ubiquitin–protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol 1, 14–19 (1999). https://doi.org/10.1038/8984
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DOI: https://doi.org/10.1038/8984
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