2592

Summary
 The Cdc25A phosphatase positively regulates cell cycle transitions; is degraded by the proteosome throughout interphase and in response to stress; and is overproduced in human cancers. The kinases targeting Cdc25A for proteolysis during early cell cycle phases have not been identified and mechanistic insight into the cause of Cdc25A overproduction in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3β (GSK-3β) phosphorylates Cdc25A to promote its proteolysis in early cell cycle phases. Phosphorylation by GSK-3β requires priming of Cdc25A and this can be catalyzed by polo-like kinase 3 (Plk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3β inactivation was observed in human tumor tissues indicating that GSK-3β inactivation may account for Cdc25A overproduction in a subset of human tumors.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA