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. Ma...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2008-06, Vol.68 (11), p.4077-4085
Main Authors: Yang, Yali, Bai, Jingxiang, Shen, Rulong, Brown, Sharron A N, Komissarova, Elena, Huang, Ying, Jiang, Ning, Alberts, Gregory F, Costa, Max, Lu, Luo, Winkles, Jeffrey A, Dai, Wei
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Line
DNA Primers
Enzyme-Linked Immunosorbent Assay
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - physiology
Immunohistochemistry
Mice
Mice, Knockout
Microscopy, Fluorescence
Protein-Serine-Threonine Kinases - physiology
Reverse Transcriptase Polymerase Chain Reaction
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-07-6182