The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression

Int J Mol Sci. 2018 Aug 5;19(8):2297. doi: 10.3390/ijms19082297.

Abstract

Hypoxia-inducible factors (HIFs) are key regulators of hypoxic responses, and their stability and transcriptional activity are controlled by several kinases. However, the regulation of HIF by protein phosphatases has not been thoroughly investigated. Here, we found that overexpression of Mg2+/Mn2+-dependent protein phosphatase 1 gamma (PPM1G), one of Ser/Thr protein phosphatases, downregulated protein expression of ectopic HIF-1α under normoxic or acute hypoxic conditions. In addition, the deficiency of PPM1G upregulated protein expression of endogenous HIF-1α under normoxic or acute oxidative stress conditions. PPM1G decreased expression of HIF-1α via the proteasomal pathway. PPM1G-mediated HIF-1α degradation was dependent on prolyl hydroxylase (PHD), but independent of von Hippel-Lindau (VHL). These data suggest that PPM1G is critical for the control of HIF-1α-dependent responses.

Keywords: HIF-1α; PPM1G; hypoxia; normoxia.

MeSH terms

  • Blotting, Western
  • Cell Hypoxia / genetics
  • Cell Hypoxia / physiology
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Protein Binding
  • Protein Phosphatase 2C / genetics
  • Protein Phosphatase 2C / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Protein Phosphatase 2C