Lack of PTEN sequesters CHK1 and initiates genetic instability

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

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 cova- lent 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.


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Academic Units
Institute for Cancer Genetics
Pathology and Cell Biology
Published Here
November 19, 2019