Journal
CANCER CELL
Volume 7, Issue 2, Pages 193-204Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2005.01.009
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Funding
- NCI NIH HHS [T32 CA09503, R01 CA082783-02, R01 CA082783, R01 CA082783-03, R01 CA082783-01A2, R01 CA082783-05, R01 CA082783-04, R01 CA82783] Funding Source: Medline
- NINDS NIH HHS [NS34746] Funding Source: Medline
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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 CHKII 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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