Lack of PTEN sequesters CHK1 and initiates genetic instability

Janusz Puc, Megan Keniry, Hong Shen Li, Tej K. Pandita, Atish D. Choudhury, Lorenzo Memeo, Mahesh Mansukhani, Vundavalli V.V.S. Murty, Zbigniew Gaciong, Sarah E.M. Meek, Helen Piwnica-Worms, Hanina Hibshoosh, Ramon Parsons

Research output: Contribution to journalArticle

263 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)193-204
Number of pages12
JournalCancer Cell
Volume7
Issue number2
DOIs
StatePublished - Feb 2005

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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