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J. Biol. Chem., Vol. 282, Issue 22, 16413-16422, June 1, 2007

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Hypoxia-inducible Factor-1, a Key Factor in the Keratinocyte Response to UVB Exposure^*

Hamid Reza Rezvani¹, Sophie Dedieu, Sophie North, Francis Belloc, Rodrigue Rossignol^¶, Thierry Letellier^¶, Hubert de Verneuil^||, Alain Taïeb^||**, and Frédéric Mazurier²

From the Inserm U876, Inserm E0113, ^¶Inserm U668, and ^||University Bordeaux, Bordeaux F-33000, France and ^**Centre Hospitalier Universitaire de Bordeaux, Department of Dermatology, National Reference Center for Rare Skin Diseases, Hôpital St. André, Bordeaux F-33000, France

Hypoxia-inducible factor-1 (HIF-1) is a major transcription factor sensitive to oxygen levels, which responds to stress factors under both hypoxic and nonhypoxic conditions. UV irradiation being a common stressor of skin, we looked at the effect of UVB on HIF-1 expression in keratinocytes. We found that UVB induces a biphasic HIF-1 variation through reactive oxygen species (ROS) generation. Whereas rapid production of cytoplasmic ROS down-regulates HIF-1 expression, delayed mitochondrial ROS generation results in its up-regulation. Indeed, activation of p38 MAPK and JNK1 mediated by mitochondrial ROS were required for HIF-1 phosphorylation and accumulation after UVB irradiation. Our experiments also revealed a key role of HIF-1 in mediating UVB-induced apoptosis. We conclude that the broad impact of the HIF-1 transcription factor on gene expression could make it a key regulator of UV-responsive genes and photocarcinogenesis.

Received for publication, December 12, 2006 , and in revised form, March 30, 2007.

^* This work was supported by Conseil Régional d'Aquitaine. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Supported by the Ministry of Science, Research, and Technology of Iran.

² To whom correspondence should be addressed: Inserm U876 Bordeaux, F-33000 France, University Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux cedex, France. Tel.: 33-557-574-766; Fax: 33-556-983-348; E-mail: mazurier{at}u-bordeaux2.fr.

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