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Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha 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-1 alpha (HIF-1 alpha) 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 alpha induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1 alpha expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1 alpha 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.

Pubmed ID: 18519666

Authors

  • Yang Y
  • Bai J
  • Shen R
  • Brown SA
  • Komissarova E
  • Huang Y
  • Jiang N
  • Alberts GF
  • Costa M
  • Lu L
  • Winkles JA
  • Dai W

Journal

Cancer research

Publication Data

June 1, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA74229
  • Agency: NHLBI NIH HHS, Id: HL39727
  • Agency: NHLBI NIH HHS, Id: HL67051
  • Agency: NHLBI NIH HHS, Id: R01 HL039727
  • Agency: NHLBI NIH HHS, Id: R01 HL067051

Mesh Terms

  • Animals
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Protein-Serine-Threonine Kinases
  • Reverse Transcriptase Polymerase Chain Reaction