The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells

Mol Cell. 2016 Oct 6;64(1):25-36. doi: 10.1016/j.molcel.2016.08.015. Epub 2016 Sep 15.


Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs. p38 phosphorylation of RB increases its affinity toward the E2F transcription factor, represses gene expression, and delays cell-cycle progression. Remarkably, introduction of a RB phosphomimetic mutant in cancer cells reduces colony formation and decreases their proliferative and tumorigenic potential in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinases / genetics*
  • Cyclin-Dependent Kinases / metabolism
  • E2F Transcription Factors / genetics*
  • E2F Transcription Factors / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Molecular Mimicry
  • Phosphorylation
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retinoblastoma Protein / chemistry
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • E2F Transcription Factors
  • Recombinant Fusion Proteins
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4