Author/Authors :
Puc، نويسنده , , Janusz and Keniry، نويسنده , , Megan and Li، نويسنده , , Hong Shen and Pandita، نويسنده , , Tej K. and Choudhury، نويسنده , , Atish D. and Memeo، نويسنده , , Lorenzo and Mansukhani، نويسنده , , Mahesh and Murty، نويسنده , , Vundavalli V.V.S. and Gaciong، نويسنده , , Zbigniew and Meek، نويسنده , , Sarah E.M. and Piwnica-Worms، نويسنده , , Helen and Hibshoosh، نويسنده , , Hanina and Parsons، نويسنده , , Ramon، نويسنده ,
Abstract :
Summary
− 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.
