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Cancer Cell. 2005 Feb;7(2):193-204.

Lack of PTEN sequesters CHK1 and initiates genetic instability.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.

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.

PMID:
15710331
DOI:
10.1016/j.ccr.2005.01.009
[Indexed for MEDLINE]
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