Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha.

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-1α under hypoxic conditions. Immunoprecipitation and pulldown analyses revealed that Plk3 physically interacted with HIF-1α under hypoxia. Purified recombinant Plk3, but not a kinase-defective mutant, phosphorylated HIF-1α 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-1α stability in vivo. Combined, our study identifies Plk3 as a new and essential player in the regulation of the hypoxia signaling pathway.
Mesh Terms:
Animals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Enzymologic, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Transgenic, Phosphorylation, Protein-Serine-Threonine Kinases, Recombinant Proteins, Signal Transduction
J. Biol. Chem.
Date: Dec. 10, 2010
Download Curated Data For This Publication
209571
Switch View:
  • Interactions 2