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J. Biol. Chem., Vol. 279, Issue 21, 21903-21915, May 21, 2004

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T Cell Receptor Signaling Inhibits Glucocorticoid-induced Apoptosis by Repressing the SRG3 Expression via Ras Activation^*

Myunggon Ko, Jiho Jang, Jeongeun Ahn, Kyuyoung Lee, Heekyoung Chung¶, Sung H. Jeon, and Rho H. Seong||

From the School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742 and the ^¶Department of Pathology, Hanyang University School of Medicine, Seoul 133-791, Korea

Activation of T cell antigen receptor (TCR) signaling inhibits glucocorticoid (GC)-induced apoptosis of T cells. However, the detailed mechanism regarding how activated T cells are protected from GC-induced apoptosis is unclear. Previously, we have shown that the expression level of SRG3, a murine homolog of BAF155 in humans, correlated well with the GC sensitivity of T cells either in vitro or in vivo. Intriguingly, the expression of SRG3 decreased upon positive selection in the thymus. Here we have shown that TCR signaling inhibits the SRG3 expression via Ras activation and thereby renders primary thymocytes and some thymoma cells resistant to GC-mediated apoptosis. By using pharmacological inhibitors, we have shown that Ras-mediated down-regulation of the SRG3 gene expression is mediated by MEK/ERK and phosphatidylinositol 3-kinase pathways. Moreover, TCR signals repressed the SRG3 transcription through the putative binding sites for E proteins and Ets family transcription factors in the proximal region of the SRG3 promoter. Introduction of mutations in these elements rendered the SRG3 promoter immune to the Ras or TCR signals. Taken together, these observations suggest that TCR signals result in GC desensitization in immature T cells by repressing SRG3 gene expression via Ras activation.

Received for publication, February 26, 2004

^* This work was supported in part by a grant from the Korea Science and Engineering Foundation through Protein Network Research Center (to R. H. S.). 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.

Supported by BK21 Program from the Ministry of Education and Human Resources Development.

^|| To whom correspondence should be addressed: School of Biological Sciences and, Institute of Molecular Biology and Genetics, Seoul National University, Kwanak-gu Shinlim-dong San 56-1, Bldg. 105, Seoul 151-742, Korea. Tel.: 82-2-880-7567; Fax: 82-2-887-9984; E-mail: rhseong{at}plaza.snu.ac.kr.

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