Abstract 2991: Glucose deprivation induces Chk1 degradation through the ubiquitin-proteasome pathway and defective checkpoint response to replication blocks

Abstract Chk1 is a key regulator for DNA replication checkpoint and preservation of genomic integrity. Previous studies showed that reduction of Chk1 function leads to defect in checkpoint response and closely associated to tumorigenesis. Here, we found that Chk1 protein is rapidly degraded upon glucose deprivation while its mRNA level is not changed. The glucose deprivation-induced Chk1 degradation is observed in various cancer cell lines as well as human normal fibroblast therefore appears to be a universal phenomenon in mammalian cells. Specific proteasome inhibitor blocks glucose deprivation-induced degradation of Chk1, and the ubiquitination of Chk1 is induced, indicating that the proteasome-ubiquitin pathway mediates the degradation of Chk1. Glucose deprivation-induced Chk1 degradation was not affected by AMPK inhibitor compound C or antioxidant NAC and GSH treatment. Instead, we found that Chk1 phosphorylation at Ser317 and Ser345 site were important step for degradation of Chk1 in response to glucose deprivation. In glucose deprivation condition, cells showed defective checkpoint response to replication stresses, camptothecin (CPT) and hydroxyurea (HU) treatment. Taken together, our results suggest that Chk1 function is suppressed through the ubiquitin-mediated proteolysis in glucose deprivation condition and thereby results in inactivation of proper checkpoint function. Glucose deprivation-induced Chk1 degradation could cause defect in maintaining DNA integrity and may contribute to tumor development in tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2991.