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 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.
Marti
A
A
Friedrich Miescher Institut, Basel, Switzerland.
Wirbelauer
C
C
Scheffner
M
M
Krek
W
W
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016193:G1 Phase; D016195:G2 Phase; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins; D013379:Substrate Specificity; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1; D044786:S-Phase Kinase-Associated Proteins; D050680:Transcription Factor DP1; D014157:Transcription Factors; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; D008025:Ligases