Lack of PTEN sequesters CHK1 and initiates genetic instability

Cancer Cell. 2005 Feb;7(2):193-204. doi: 10.1016/j.ccr.2005.01.009.

Abstract

Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p <0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Cytoplasm / metabolism
  • DNA Damage
  • Embryo, Mammalian / cytology
  • G2 Phase
  • Growth Substances / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Models, Genetic
  • Mutation
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Kinases / genetics*
  • Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Radiation, Ionizing
  • Serine / chemistry
  • Signal Transduction
  • Stem Cells / cytology
  • Time Factors
  • Ubiquitin / metabolism

Substances

  • Growth Substances
  • Proto-Oncogene Proteins
  • Ubiquitin
  • Serine
  • Protein Kinases
  • AKT1 protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases