Acetylation control of the retinoblastoma tumour-suppressor protein

Nat Cell Biol. 2001 Jul;3(7):667-74. doi: 10.1038/35083062.

Abstract

The retinoblastoma tumour-suppressor protein (pRb) and p300/CBP co-activator proteins are important for control of proliferation and in tumour cells these are sequestered by viral oncoproteins such as E1A. pRb is involved in negatively regulating growth, and p300/CBP proteins have histone acetyltransferase (HAT) activity, which influences gene expression. Although it is known that phosphorylation by G1 cyclin-dependent kinases (CDKs) regulates pRb activity, the nature and role of other post-translational modifications is not understood. Here we identify acetylation as a new type of modification and level of control in pRb function. Adenovirus E1A, which binds p300/CBP through an amino-terminal transformation-sensitive domain, stimulates the acetylation of pRb by recruiting p300 and pRb into a multimeric-protein complex. Furthermore, pRb acetylation is under cell-cycle control, and acetylation hinders the phosphorylation of pRb by cyclin-dependent kinases. pRb binds more strongly when acetylated to the MDM2 oncoprotein, which indicates that acetylation may regulate protein-protein interactions in the pRb pathway. The acetylation of pRb defines a new level of cell-cycle control mediated by HAT. Furthermore, our results establish a relationship between p300, pRb and acetylation in which E1A acts to recruit and target a cellular HAT activity to pRb.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Adenovirus E1A Proteins / pharmacology
  • Cell Cycle / drug effects
  • Growth Inhibitors / metabolism
  • Growth Inhibitors / pharmacology
  • Humans
  • Mutation
  • Nuclear Proteins / pharmacology
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Retinoblastoma Protein / pharmacology
  • Trans-Activators / pharmacology
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Adenovirus E1A Proteins
  • Growth Inhibitors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Trans-Activators
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2