Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint.
Commitment of mammalian cells to enter S phase enables the transcription factor E2F-1 to activate certain genes whose products mediate cell cycle advance. In S phase, E2F-1 forms stable complexes with cyclin A-kinase, which in turn eliminates E2F-1DNA binding function. Here, we show that suppression of E2F-1 DNA-binding activity by cyclin A-kinase is linked to orderly S phase progression. Disruption of this linkage resulted in S phase delay/arrest followed by regrowth or apoptosis, depending upon whether the DNA-bound E2F-1 could transactivate. Hence, the unscheduled presence of E2F-1 on specific DNA sequences during S phase can activate a specific S phase checkpoint, thereby linking transcription, DNA replication, and cell cycle control.
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
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D016475:3T3 Cells / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D016213:Cyclins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
C533431:Arid4a protein, mouse; D001798:Blood Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases