Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling

Brooke M. Emerling, Leonidas C. Platanias, Emma Black, Angel R. Nebreda, Roger J. Davis, Navdeep S. Chandel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

Abstract

Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38α-/- cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38α, also fail to activate HIF-1 under hypoxic conditions. The p38α-/- cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38a and HIF-1 was abolished by myxothiazol, a mitochondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38a and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.

Original languageEnglish (US)
Pages (from-to)4853-4862
Number of pages10
JournalMolecular and cellular biology
Volume25
Issue number12
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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