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



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



Molecular and Cellular Biology 25(12): 4853-4862



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 p38alpha-/- cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38alpha, also fail to activate HIF-1 under hypoxic conditions. The p38alpha-/- cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38alpha 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 p38alpha 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.

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Accession: 012311131

Download citation: RISBibTeXText

PMID: 15923604

DOI: 10.1128/mcb.25.12.4853-4862.2005


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