The glucocorticoid-induced gene tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation promotes glucocorticoid-induced apoptosis.
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.
Malone
Michael H
MH
Department of Medicine, Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
Wang
Zhengqi
Z
Distelhorst
Clark W
CW
D000465:Algorithms; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000737:chemistry*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000188:drug therapy; D008214:Lymphocytes / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D020411:Oligonucleotide Array Sequence Analysis; D011609:Psychosine / Q000494:pharmacology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology*; D013110:Sphingosine / Q000737:chemistry
C513334:GPR65 protein, human; C513337:GPR65 protein, mouse; D005938:Glucocorticoids; D043562:Receptors, G-Protein-Coupled; D049452:Green Fluorescent Proteins; D011609:Psychosine; D003907:Dexamethasone; D013110:Sphingosine