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J. Biol. Chem., Vol. 280, Issue 45, 37725-37731, November 11, 2005

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Glucocorticoid-induced Tumor Necrosis Factor Receptor Is a p21^Cip1/WAF1 Transcriptional Target Conferring Resistance of Keratinocytes to UV Light-induced Apoptosis^*

Jian Wang1, Vikram Devgan1, Marcella Corrado, Nita S. Prabhu¶, Wafik S. El-Deiry¶, Carlo Riccardi||, Pier Paolo Pandolfi**, Caterina Missero, and G. Paolo Dotto2

From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, Telethon Institute of Genetics and Medicine, 80131 Naples, Italy, ^¶Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ^||Department of Clinical and Experimental Medicine, Pharmacology Section, Perugia University Medical School, Perugia, Italy, ^**Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and the Department of Biochemistry, University of Lausanne, Epalinges 1066 CH, Switzerland

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor superfamily, is expressed in T lymphocytes, and exerts an anti-apoptotic function in these cells. We reported that GITR is also highly expressed in the skin, specifically in keratinocytes, and that it is under negative transcriptional control of p21^Cip1/WAF1, independently from the cell cycle. Although GITR expression is higher in p21-deficient keratinocytes and skin, it is down-modulated with differentiation and in response to UVB. The combined analysis of keratinocytes with increased GITR expression versus normal keratinocytes and skin of mice with a disruption of the GITR gene indicates that this protein protects keratinocytes from UVB-induced apoptosis both in vitro and in vivo.

Received for publication, July 21, 2005 , and in revised form, August 15, 2005.

^* This work was supported by National Institutes of Health Grants AR39190, CA16038, and CA73796 and a grant from the Swiss National Foundation (to G. P. D.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry, University of Lausanne, Chemin de Boveresses 155, CH-1066 Epalinges, Switzerland. Tel.: 41-21-692-5720; Fax: 41-216925705; E-mail: gdotto{at}partners.org.

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