Lack of PTEN sequesters CHK1 and initiates genetic instability

Puc, J. et al. (2005) Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell, 7(2), pp. 193-204. (doi: 10.1016/j.ccr.2005.01.009)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Meek, Dr Sarah
• Authors: Puc, J., Keniry, M., Li, H. S., Pandita, T. K., Choudhury, A. D., Memeo, L., Mansukhani, M., Murty, V. V.V.S., Gaciong, Z., Meek, S., Piwnica-Worms, H., Hibshoosh, H., and Parsons, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Cancer Cell
• Publisher: Elsevier
• ISSN: 1535-6108
• ISSN (Online): 1878-3686