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

Abstract

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.

Thioredoxin-interacting protein (txnip) is a glucocorticoid-regulated primary response gene involved in mediating glucocorticoid-induced apoptosis

“…Primary thymocytes undergo apoptosis within 8-12 h of exposure to Dex, whereas in S49.A2 and WEHI7.2 cells apoptosis is delayed for over 24 h (Wang et al, 2003a, b). Through oligonucleotide microarray analysis, we have identified three apoptosis-related genes induced by Dex in all three model systems: bim, dig2, and tdag8 (Wang et al, 2003a, b;Malone et al, 2004). Now, in the present study, which is also based on microarray findings, we show that the gene encoding thioredoxin-interacting protein (TXNIP), a natural inhibitor of the antioxidant protein thioredoxin, is rapidly induced by Dex in each of the model systems.…”

“…We have used oligonucleotide microarrays to identify glucocorticoid-regulated genes in three separate but related model systems: the S49.A2 and WEHI7.2 murine T-cell lymphoma lines, and primary murine thymocytes (Wang et al, 2003a, b;Malone et al, 2004). Dexamethasone (Dex) induces apoptosis in all three systems, although with different kinetics.…”

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

“…Many of the dexamethasoneinduced genes found in this study have been previously reported in similar screens, including Tdag8, 18,19 Fkbp51, 19 Dig2 20 and Bim. 19,20 Overexpression of these genes changes susceptibility to apoptosis and also changes sensitivity to dexamethasone in a variety of systems. We, therefore, first addressed if the genes identified in this screen could regulate the survival of developing thymocytes.…”

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

“…Gpr65 encodes a proapoptotic G protein-coupled receptor that promotes glucocorticoidinduced apoptosis. Activation of Gpr65 by its agonist psychosine markedly enhanced dexamethasone-induced apoptosis in a Gpr65-dependent manner (45). Upregulation of Gpr65 in human tumors is involved in driving or maintaining tumor formation (46).…”