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J. Biol. Chem., Vol. 278, Issue 38, 35950-35958, September 19, 2003

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Structure/Function Analysis of the Murine CD95L Promoter Reveals the Identification of a Novel Transcriptional Repressor and Functional CD28 Response Element^*

Scott A. Crist, Thomas S. Griffith and Timothy L. Ratliff 

From the Department of Urology and the Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa 52242

CD28 costimulation, an important second signal for antigen-mediated T cell activation, is known to enhance expression of several genes important for the regulation of CD4+ T cell effector function including interleukin-2 and CD154. Previous studies demonstrate CD28-mediated enhancement of the transcription and expression of Fas ligand (CD95L) in T cell lines, suggesting a regulatory link between CD28 and CD95L expression. These results served as the basis for structure/function analysis of the CD95L promoter to elucidate the mechanism for CD28-mediated enhancement of CD95L. In this report, we describe a novel response element, located at -210 to -201 bp upstream of the transcription start site, that confers CD28 responsiveness to the CD95L gene. This response element is homologous to the CD28 response element (CD28RE) previously identified in the IL-2 promoter and bears structural similarities to a newly identified CD28RE in the CD154 promoter. We further demonstrate that CD28-mediated enhancement of promoter activity correlates with enhanced expression of CD95L mRNA, cell surface expression of CD95L protein, and increased apoptosis of CD95+ target cells. These results demonstrate a direct transcriptional regulatory role for CD28 in CD95L-mediated functional activity in CD4+ T cells. Mutational analysis of the CD95L promoter also reveals a novel transcriptional repressor element located 60 bp 5' of the CD28RE. The repressor element bears sequence homology to an activator protein-1 element, constitutively binds c-Fos but not c-Jun, and is activation-independent.

Received for publication, June 12, 2003 , and in revised form, July 9, 2003.

^* 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.

To whom correspondence should be addressed: Dept. of Urology, 3206 MERF, Iowa City, IA 52245. Tel.: 319-335-8107; Fax: 319-353-4556; E-mail: Tim-Ratliff{at}uiowa.edu.

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