Abstract
Nur77 (NGFI-B) is an orphan nuclear receptor that has been implicated in activation-induced T-cell apoptosis. Retinoids, potent immune modulators, were shown to inhibit the activation-induced apoptosis of immature thymocytes and T-cell hybridomas. To illustrate the mechanism of the inhibition, we examined the effects of retinoic acid (RA) on the expression and transactivation functions of Nur77 in the human peripheral blood mononuclear cells and the human T-cell leukemia, Jurkat. All-trans-RA remarkably repressed the DNA binding and transcriptional induction of Nur77. Among the two potential trans-acting factors that activate Nur77 gene promoter, i.e., AP-1 and related serum response factor (RSRF), all-trans-RA repressed DNA binding and reporter gene activity of AP-1 but not that of RSRF, suggesting that the inhibition may be mediated through AP-1. We also demonstrated a posttranscriptional regulation of Nur77 function by retinoid receptors by showing that transactivation activity of Nur77 was significantly inhibited by cotransfection of RARα or RXRα. Nur77 bound RARα or RXRα in both yeast and mammalian two-hybrid tests, suggesting that direct protein-protein interaction between these receptors may mediate the inhibition. Taken all together, we demonstrated that RA repressed Nur77 function through multiple mechanisms that may provide the basis for RA inhibition on the apoptosis of activated T-lymphocytes. (C) 2000 Academic Press.
Original language | English |
---|---|
Pages (from-to) | 545-554 |
Number of pages | 10 |
Journal | Experimental Cell Research |
Volume | 256 |
Issue number | 2 |
DOIs | |
State | Published - 1 May 2000 |
Bibliographical note
Funding Information:We thank Drs. Astar Winoto and Jacques Drouin for the reporter constructs, i.e., Nur77 promoter-CAT and NurRE-pomc-Luc, respectively. We also thank Dr. Xiao-kun Zhang for the Nur77 expression vector and the purified GST-Flag-Nur77 protein. This work was supported by grants from KOSEF (96-0403-15-01-3) and from the Korea Research Foundation (1998-019-F00009) to M.-O. Lee. J.W.L. is supported by the National Creative Research Initiatives Program of the Korean Ministry of Science and Technology.
Keywords
- Apoptosis
- Nur77
- RAR
- RXR
- Retinoic acid
- T-lymphocytes