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.
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Yali
Y
Yang
Jingxiang
J
Bai
Rulong
R
Shen
Sharron A N
SA
Brown
Elena
E
Komissarova
Ying
Y
Huang
Ning
N
Jiang
Gregory F
GF
Alberts
Max
M
Costa
Luo
L
Lu
Jeffrey A
JA
Winkles
Wei
W
Dai
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C093328:Plk3 protein, mouse; D017346:Protein Serine-Threonine Kinases