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Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.

We present evidence that phosphorylation of the C-terminal region of Rb by Cdk4/6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by Rb. This facilitates a second interaction that leads to phosphorylation of the pocket by Cdk2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of Rb by Cdk4/6 and Cdk2. Cdk4/6 is activated early in G1, blocking active repression by Rb. However, it is not until near the end of G1, when cyclin E is expressed and Cdk2 is activated, that Rb is prevented from binding and inactivating E2F.

Pubmed ID: 10499802

Authors

  • Harbour JW
  • Luo RX
  • Dei Santi A
  • Postigo AA
  • Dean DC

Journal

Cell

Publication Data

September 17, 1999

Associated Grants

None

Mesh Terms

  • CDC2-CDC28 Kinases
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin E
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Female
  • G1 Phase
  • Gene Expression Regulation
  • Histone Deacetylases
  • Humans
  • Lysine
  • Mutation
  • Peptide Fragments
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Transcription, Genetic
  • Tumor Cells, Cultured