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The E2F proteins form a family of transcription factors that regulate the transition from the G1 to the S phase in the cell cycle. E2F activity is regulated by members of the retinoblastoma protein (pRb) family, ensuring the tight control of E2F-responsive genes. During the G1 phase, phosphorylation of pRb by cyclin-dependent kinases (CDKs), most notably cyclin D-CDK complexes, releases pRb from E2F, facilitating cell-cycle progression by the timely induction of E2F-targeted genes such as cyclin E. However, it is not known whether E2F proteins are directly targeted by CDKs. Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that E2F activity may be directly regulated by cyclin E-Cdk2, and imply an autoregulatory mechanism for cell-cycle-dependent transcription through the CDK-stimulated interaction of E2F with p300/CBP co-activators.

Original publication




Journal article


Nat Cell Biol

Publication Date





232 - 239


Animals, CDC2-CDC28 Kinases, CREB-Binding Protein, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cells, Cultured, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, DNA-Binding Proteins, E2F Transcription Factors, E2F5 Transcription Factor, G1 Phase, Gene Expression Regulation, Enzymologic, Homeostasis, Nuclear Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Recombinant Proteins, Retinoblastoma-Binding Protein 1, S Phase, Threonine, Trans-Activators, Transcription Factors, Transcriptional Activation