Abstract
Hypoxia inhibits Na-K-ATPase activity and leads to its degradation in mammalian cells. Von Hippel Lindau protein (pVHL) and hypoxia inducible factor (HIF) are key mediators in cellular adaptation to hypoxia; thus, we set out to investigate whether pVHL and HIF participate in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase. We found that in the presence of pVHL hypoxia decreased Na-K-ATPase activity and promoted the degradation of plasma membrane Na-K-ATPase. In pVHL-deficient cells, hypoxia did not decrease the Na-K-ATPase activity and the degradation of plasma membrane Na-K-ATPase was prevented. pVHL-mediated degradation of Na-K-ATPase required the functional pVHL E3 ligase and Ubc5 since pVHL mutants and dominant-negative Ubc5 prevented Na-K-ATPase from degradation. The generation of reactive oxygen species was necessary for pVHL-mediated Na-K-ATPase degradation during hypoxia. Desferrioxamine, which stabilizes HIF1/2α, did not affect the half-life of plasma membrane Na-K-ATPase. In addition, stabilizing HIF1/2α by infecting mammalian cells with adenoviruses containing the oxygen-dependent degradation domain of HIF1α did not affect the plasma membrane Na-K-ATPase degradation. In cells with suppression of pVHL by short hairpin RNA, the Na-K-ATPase was not degraded during hypoxia, whereas cells with knockdown of HIF1/2α retained the ability to degrade plasma membrane Na-K-ATPase. These findings suggest that pVHL participates in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase in a HIFindependent manner.
Original language | English (US) |
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Pages (from-to) | 1335-1342 |
Number of pages | 8 |
Journal | FASEB Journal |
Volume | 22 |
Issue number | 5 |
DOIs | |
State | Published - May 2008 |
Keywords
- Hypoxia inducible factor
- pVHL
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics