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J. Biol. Chem., Vol. 279, Issue 51, 52850-52859, December 17, 2004

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The Glucocorticoid-induced Gene tdag8 Encodes a Pro-apoptotic G Protein-coupled Receptor Whose Activation Promotes Glucocorticoid-induced Apoptosis^*

Michael H. Malone, Zhengqi Wang, and Clark W. Distelhorst

From the Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106

The apoptotic action of glucocorticoids on lymphocytes makes them effective therapeutics for many lymphoid malignancies. Although it is clear that glucocorticoid-induced apoptosis requires transcription, the gene products that induce apoptosis remain unknown. Using gene expression profiles of lymphoma cell lines and primary thymocytes treated with the synthetic glucocorticoid dexamethasone, we discovered that induction of tdag8 (T-cell death-associated gene 8) was a common event in each model system investigated. Activation of TDAG8 by its agonist psychosine markedly enhanced dexamethasone-induced apoptosis in a TDAG8-dependent manner. Expression of a TDAG8-GFP fusion protein was sufficient to induce apoptosis, and repression of endogenous TDAG8 using RNA interference partially inhibited dexamethasone-induced apoptosis. Together, these data suggest that TDAG8 is a regulator of glucocorticoid-induced apoptosis and that agonists of TDAG8 may be promising agents to improve the efficacy of glucocorticoids for the treatment of leukemia and lymphoma.

Received for publication, July 16, 2004 , and in revised form, October 6, 2004.

^* This work was supported by Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland Grant P30 CA43703 and National Institutes of Health Grants R01 CA042755-17 (to C. W. D.) and T32 CA059366-10 (to M. H. M.). 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: Comprehensive Cancer Center, Case Western Reserve University School of Medicine, WRB 3–133, 10900 Euclid Ave., Cleveland, OH 44106-7285. Tel.: 216-368-4546; Fax: 216-368-8919; E-mail: cwd{at}po.cwru.edu.

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