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Molecular and Cellular Biology, March 2002, p. 1734-1741, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1734-1741.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1, Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia

Konstantin Salnikow,1* Thomas Kluz,1 Max Costa,1 David Piquemal,2 Zoya N. Demidenko,3 Keping Xie,4 and Mikhail V. Blagosklonny3

Department of Environmental Medicine, NIEHS Center, and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016,1 Université Montpellier II, 34095 Montpellier Cedex 05, France,2 Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892,3 Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 770304

Received 15 October 2001/ Accepted 20 November 2001

Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca2+) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca2+ neither induced the HIF-1{alpha} protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca2+ induced NDRG-1/Cap43 mRNA in HIF-1{alpha}-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca2+ ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca2+-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca2+-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca2+ activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia.

* Corresponding author. Mailing address: 550 First Ave., Department of Environmental Medicine, NIEHS and Kaplan Comprehensive Cancer Centers, NYU, New York, NY 10016. Phone: (845) 731-3516. Fax: (845) 351-2118. E-mail: salnikow{at}env.med.nyu.edu.

Molecular and Cellular Biology, March 2002, p. 1734-1741, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1734-1741.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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