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

Nat Cell Biol. 2000 Apr;2(4):232-9. doi: 10.1038/35008660.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin E
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F5 Transcription Factor
  • Nuclear Proteins
  • Recombinant Proteins
  • Retinoblastoma-Binding Protein 1
  • Trans-Activators
  • Transcription Factors
  • Threonine
  • CREB-Binding Protein
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases