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Molecular and Cellular Biology, June 2005, p. 4853-4862, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4853-4862.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling

Brooke M. Emerling,1 Leonidas C. Platanias,1 Emma Black,2 Angel R. Nebreda,2 Roger J. Davis,3 and Navdeep S. Chandel1*

Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611,1 European Molecular Biology Laboratory, 69117 Heidelberg, Germany,2 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 016053

Received 5 October 2004/ Returned for modification 13 December 2004/ Accepted 22 March 2005

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 p38{alpha}–/– cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38{alpha}, also fail to activate HIF-1 under hypoxic conditions. The p38{alpha}–/– cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38{alpha} 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 p38{alpha} 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.

* Corresponding author. Mailing address: McGaw Pavilion, 240 East Huron Avenue, 2nd Floor, Northwestern University Medical School, Chicago, IL 60611. Phone: (312) 503-2549. Fax: (312) 908-4650. E-mail: nav{at}northwestern.edu.

Molecular and Cellular Biology, June 2005, p. 4853-4862, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4853-4862.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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