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J. Biol. Chem., Vol. 282, Issue 22, 16187-16201, June 1, 2007

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In Cultured Astrocytes, p53 and MDM2 Do Not Alter Hypoxia-inducible Factor-1 Function Regardless of the Presence of DNA Damage^*

David A. Rempe¹, Katherine M. Lelli, Grace Vangeison, Randall S. Johnson, and Howard J. Federoff

From the Department of Neurology, Center for Aging and Developmental Biology, and the Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 and the Department of Biology, University of California, San Diego, California 92093

A principal molecular mechanism by which cells respond to hypoxia is by activation of the transcription factor hypoxia-inducible factor 1 (HIF-1). Several studies describe a binding of p53 to HIF-1 in a protein complex, leading to attenuated function, half-life, and abundance of HIF-1. However, these reports almost exclusively utilized transformed cell lines, and many employed transfection of p53 or HIF-1 plasmid constructs and/or p53 and HIF-1 reporter constructs as surrogates for endogenous protein activity and target expression, respectively. Thus, it remains an open and important question as to whether p53 inhibits HIF-1-mediated transactivation of endogenous HIF-1 targets in nontransformed cells. After determining in primary astrocyte cultures the HIF-1 targets that were most dependent on HIF-1 function, we examined the effect of the loss of p53 function either alone or in combination with MDM2 on expression of these targets. Although p53 null astrocyte cultures resulted in markedly increased HIF-1-dependent target expression compared with controls, this altered expression was determined to be the result of increased cell density of p53 null cultures and the accompanying acidosis, not loss of p53 protein. Although activation of p53 by DNA damage induced p53 target expression in astrocytes, it did not alter hypoxia-induced HIF-1 target expression. Finally, a combined loss of MDM2 and p53 did not alter HIF-1 target expression compared with loss of p53 alone. These data strongly suggest that p53 and MDM2 do not influence the hypoxia-induced transactivation of HIF-1 targets, regardless of p53 activation, in primary astrocytes.

Received for publication, March 14, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center for Aging and Developmental Biology, Box 645, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-2530; Fax: 585-506-1957; E-mail: david_rempe{at}urmc.rochester.edu.

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