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Regulation of E2F transcription by cyclin E–Cdk2 kinase mediated through p300/CBP co-activators

Nature Cell Biology volume 2, pages 232–239 (2000)Cite this article

Abstract

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.

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Figure 1: E2F-5 is regulated by phosphorylation during cell-cycle progression.
Figure 2: Mutant derivatives of E2F-5.
Figure 3: A threonine residue at position 251 of E2F-5 is phosphorylated by cyclin E–Cdk2.
Figure 4: Cyclin E–Cdk2 stimulates E2F-5-dependent transcription.
Figure 5: Cyclin E–Cdk2 augments the interaction of p300 with E2F-5.
Figure 6: CDK regulation of E2F activity.

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Acknowledgements

We thank M. Eilers and D. Morgan for reagents, W. Kolch for advice on phosphopeptide mapping, M. Krstic-Demonacos and N. Shikama for comments on the manuscript and M. Caldwell for help in preparing the manuscript. This research was supported by the U.K. Medical Research Council, the Leukaemia Research Fund and the European Union.

Correspondence and requests for materials should be addressed to N.B.L.

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  1. K. Elizabeth Allen

    Present address: Rhône-Polenc Rorer Ltd, Dagenham, RM10 7XS, UK

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  1. Division of Biochemistry and Molecular Biology, University of Glasgow, Davidson Building, Glasgow, G12 8QQ, UK

    Lorna Morris, K. Elizabeth Allen & Nicholas B. La Thangue

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Morris, L., Allen, K. & La Thangue, N. Regulation of E2F transcription by cyclin E–Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol 2, 232–239 (2000). https://doi.org/10.1038/35008660

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