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

¹ Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York; ² Department of Pathology, Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, Ohio; ³ Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; ⁴ New York Medical College, Valhalla, New York; and ⁵ Division of Molecular Medicine, Harbor-University of California at Los Angeles Medical Center, Torrance, California

Requests for reprints: Wei Dai, Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987. Phone: 845-731-3555; Fax: 845-731-3611; E-mail: wei.dai{at}med.nyu.edu.

Key Words: Plk3 • Polo-like kinases • tumorigenesis • hypoxia • HIF-1 • mouse genetics

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-1 (HIF-1) 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-1 induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1 expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1 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]

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