Data from Polo-like Kinase 3 Functions as a Tumor Suppressor and Is a Negative Regulator of Hypoxia-Inducible Factor-1α under Hypoxic Conditions

Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In this study, we examined the physiologic function of Plk3 by generating Plk3-deficient mice. Plk3−/− mice displayed an increase in weight and developed tumors in various organs at advanced age. Many tumors in Plk3−/− mice were large in size, exhibiting enhanced angiogenesis. Plk3−/− mouse embryonic fibroblasts were hypersensitive to the induction of hypoxia-inducible factor-1α (HIF-1α) under hypoxic conditions or by nickel and cobalt ion treatments. Ectopic expression of the Plk3-kinase domain (Plk3-KD), but not its Polo-box domain or a Plk3-KD mutant, suppressed the nuclear accumulation of HIF-1α induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1α expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1α in mediating the activation of the “survival machinery” in cancer cells, these studies strongly suggest that enhanced tumorigenesis in Plk3-null mice is at least partially mediated by a deregulated HIF-1 pathway. [Cancer Res 2008;68(11):4077–85]