Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor-mediated transcription.
Glucocorticoid-induced apoptosis of thymocytes is one of the first recognized forms of programmed cell death. It was shown to require gene activation induced by the glucocorticoid receptor (GR) translocated into the nucleus following ligand binding. In addition, the necessity of the glucocorticoid-induced, but transcription-independent phosphorylation of phosphatidylinositol-specific phospholipase C (PI-PLC) has also been shown. Here we report that retinoic acids, physiological ligands for the nuclear retinoid receptors, enhance glucocorticoid-induced death of mouse thymocytes both in vitro and in vivo. The effect is mediated by retinoic acid receptor (RAR) alpha/retinoid X receptor (RXR) heterodimers, and occurs when both RARα and RXR are ligated by retinoic acids. We show that the ligated RARα/RXR interacts with the ligated GR, resulting in an enhanced transcriptional activity of the GR. The mechanism through which this interaction promotes GR-mediated transcription does not require DNA binding of the retinoid receptors and does not alter the phosphorylation status of Ser232, known to regulate the transcriptional activity of GR. Phosphorylation of PI-PLC was not affected. Besides thymocytes, retinoids also promoted glucocorticoid-induced apoptosis of various T-cell lines, suggesting that they could be used in the therapy of glucocorticoid-sensitive T-cell malignancies.
Apoptosis and Genomics Research Group, Department of Biochemistry and Molecular Biology, Hungarian Academy of Sciences, University of Debrecen, Nagyerdei krt. 98, Debrecen, Hungary.
K
K
Tóth
Z
Z
Sarang
B
B
Scholtz
P
P
Brázda
N
N
Ghyselinck
P
P
Chambon
L
L
Fésüs
Z
Z
Szondy
D000077556:Alitretinoin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000009:adverse effects; D017353:Gene Deletion; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000494:pharmacology; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
C498608:Dsip1 protein, mouse; D005938:Glucocorticoids; C423914:LG 268; D009930:Organic Chemicals; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D003907:Dexamethasone; D054801:Phosphoinositide Phospholipase C