Abstract
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.
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Abbreviations
- ATRA:
-
all-trans retinoic acid
- 9cRA:
-
9-cis retinoic acid
- GR:
-
glucocorticoid receptor
- PI-PLC:
-
phosphatidylinositol-specific phospholipase C
- RAR:
-
retinoic acid receptor
- RXR:
-
retinoid X receptor
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Acknowledgements
This work was supported by Hungarian National Research Fund (OTKA T049445, K 77587 and NI 67877), Ministry of Welfare T (115/2006), EU (MRTN-CT-2006-036032 and 2006-035624, LSHB-CT-2007-037730) and TÁMOP 4.2.1./B-09/1/KONV-2010-0007 project. The latest project is implemented through the New Hungary Development Plan, co-financed by the European Social Fund. We thank the Galderma Research & Development for providing the retinoid receptor ligands. The technical assistance of Edit Komóczi and Zsolt Hartmann is gratefully acknowledged.
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Tóth, K., Sarang, Z., Scholtz, B. et al. Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor-mediated transcription. Cell Death Differ 18, 783–792 (2011). https://doi.org/10.1038/cdd.2010.136
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DOI: https://doi.org/10.1038/cdd.2010.136
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