Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha.
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Xu D, Yao Y, Lu L, Costa M, Dai W
Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha.
J Biol Chem. 2010 Dec 10;285(50):38944-50. doi: 10.1074/jbc.M110.160325. Epub 2010 Oct 1.
- PubMed ID
- 20889502 [ View in PubMed]
- Abstract
Polo-like kinase 3 (Plk3) plays an important role in the regulation of cell cycle progression and stress responses. Plk3 also has a tumor-suppressing activity as aging PLK3-null mice develop tumors in multiple organs. The growth of highly vascularized tumors in PLK3-null mice suggests a role for Plk3 in angiogenesis and cellular responses to hypoxia. By studying primary isogenic murine embryonic fibroblasts, we tested the hypothesis that Plk3 functions as a component in the hypoxia signaling pathway. PLK3(-/-) murine embryonic fibroblasts contained an enhanced level of HIF-1alpha under hypoxic conditions. Immunoprecipitation and pulldown analyses revealed that Plk3 physically interacted with HIF-1alpha under hypoxia. Purified recombinant Plk3, but not a kinase-defective mutant, phosphorylated HIF-1alpha in vitro, resulting in a major mobility shift. Mass spectrometry identified two unique serine residues that were phosphorylated by Plk3. Moreover, ectopic expression followed by cycloheximide or pulse-chase treatment demonstrated that phospho-mutants exhibited a much longer half-life than the wild-type counterpart, strongly suggesting that Plk3 directly regulates HIF-1alpha stability in vivo. Combined, our study identifies Plk3 as a new and essential player in the regulation of the hypoxia signaling pathway.