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

Cell. 1999 Sep 17;98(6):859-69. doi: 10.1016/s0092-8674(00)81519-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin E
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • Histone Deacetylases
  • Lysine