PRAK is essential for ras-induced senescence and tumor suppression

Cell. 2007 Jan 26;128(2):295-308. doi: 10.1016/j.cell.2006.11.050.

Abstract

Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38-regulated/activated protein kinase (PRAK) is a p38 MAPK substrate whose physiological functions are poorly understood. Here we describe a role for PRAK in tumor suppression by demonstrating that PRAK mediates senescence upon activation by p38 in response to oncogenic ras. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis, coinciding with compromised senescence induction. In primary cells, inactivation of PRAK prevents senescence and promotes oncogenic transformation. Furthermore, we show that PRAK activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by PRAK following activation of p38 MAPK by ras plays an important role in ras-induced senescence and tumor suppression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / genetics
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • MAP-kinase-activated kinase 5
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins