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Molecular and Cellular Biology, April 2002, p. 2515-2523, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2515-2523.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Response of c-Jun/AP-1 to Chronic Hypoxia Is Hypoxia-Inducible Factor 1{alpha} Dependent

Keith R. Laderoute,1* Joy M. Calaoagan,1 Cindy Gustafson-Brown,2 A. Merrill Knapp,1 Guo-Chun Li,2 Holly L. Mendonca,1 Heather E. Ryan,2 Zhaohui Wang,1 and Randall S. Johnson2

Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025,1 Molecular Biology Section, Division of Biology, University of California, San Diego, La Jolla, California 921382

Received 11 September 2001/ Returned for modification 1 November 2001/ Accepted 22 January 2002

Hypoxia (low-oxygen tension) is an important physiological stress that influences responses to a wide range of pathologies, including stroke, infarction, and tumorigenesis. Prolonged or chronic hypoxia stimulates expression of the stress-inducible transcription factor gene c-jun and transient activation of protein kinase and phosphatase activities that regulate c-Jun/AP-1 activity. Here we describe evidence obtained by using wild-type and HIF-1{alpha} nullizygous mouse embryonic fibroblasts (mEFs) that the induction of c-jun mRNA expression and c-Jun phosphorylation by prolonged hypoxia are completely dependent on the presence of the oxygen-regulated transcription factor hypoxia-inducible factor 1{alpha} (HIF-1{alpha}). In contrast, transient hypoxia induced c-jun expression in both types of mEFs, showing that the early or rapid induction of this gene is independent of HIF-1{alpha}. These findings indicate that the c-jun gene has a biphasic response to hypoxia consisting of inductions that depend on the degree or duration of exposure. To more completely define the relationship between prolonged hypoxia and c-Jun phosphorylation, we used mEFs from mice containing inactivating mutations of critical phosphorylation sites in the c-Jun N-terminal region (serines 63 and 73 or threonines 91 and 93). Exposure of these mEFs to prolonged hypoxia demonstrated an absolute requirement for N-terminal sites for HIF-1{alpha}-dependent phosphorylation of c-Jun. Taken together, these findings suggest that c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in pathophysiological microenvironments.

* Corresponding author. Mailing address: SRI International, Bldg. L, Rm. A258, 333 Ravenswood Ave., Menlo Park, CA 94025. Phone: (650) 859-3080. Fax: (650) 859-5816. E-mail: keith.laderoute{at}sri.com.

Molecular and Cellular Biology, April 2002, p. 2515-2523, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2515-2523.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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