Abstract 1005: Plk3 functions as an essential component of the survival and hypoxia regulatory pathway by direct phosphorylation and regulation of PTEN and HIF-1α

Abstract

Abstract Plk3, a member of the Polo-like kinase family, plays an important role in regulating cell cycle progression and cell cycle checkpoints in response to genotoxic stresses. Plk3 is also strongly implicated in tumorigenesis because PLK3-/- mice develop tumors in multiple organs at an enhanced rate. We have previously shown that many of the tumors developed in the PLK3 null mice are large in size and are highly vascularized, suggesting that this kinase may be involved in regulating the angiogenesis pathway. By studying PLK3 null primary isogenic murine embryonic fibroblasts (MEFs), we tested the hypothesis that Plk3 functions as a component in the hypoxia signaling pathway. PLK3-/- MEFs contained a reduced level and activity of PTEN that closely correlated with increased PDK1 and Akt1 activation as well as decreased GSK3β activity. The activated Akt1 in PLK3 null MEFs was closely associated with enhanced stability of HIF-1α under hypoxic conditions. Purified recombinant Plk3 phosphorylated PTEN and HIF-1α in vitro and phospho-mutant analysis indicated that Plk3 directly regulates these proteins in vivo. Combined, our study identifies Plk3 as a new and essential player in the regulation of the hypoxia and angiogenesis signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1005. doi:10.1158/1538-7445.AM2011-1005