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

• DOI: 10.1016/j.molcel.2016.08.015
• Publication Date: 2016-09-16T03:33:24Z
• Authors: Albert Gubern; Manel Joaquin; Miriam Marquès; Pedro Maseres; Javier Garcia-Garcia; Ramon Amat; Daniel González-N...; Baldo Oliva; Francisco X. Real; Eulàlia de Nadal; Francesc Posas
• Keywords: 0301 basic medicine; MAP Kinase Kinase 4; Recombinant Fusion Proteins; Molecular Mimicry; Breast Neoplasms; Epithelial Cells; Retinoblastoma Protein; Xenograft Model Antitumor Assays; Cyclin-Dependent Kinases; Protein Structure, Secondary; E2F Transcription Factors; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Female; Protein Interaction Domains and Motifs; Phosphorylation; Cell Proliferation; Signal Transduction

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.