Retinoic acid and its receptors repress the expression and transactivationfunctions of Nur77: A possible mechanism for the inhibition of apoptosis by retinoic acid

Nur77 (NGFI-B) is an orphan. nuclear receptor that has been implicated in a ctivation-induced T-cell apoptosis. Retinoids, potent immune modulators, we re shown to inhibit the activation-induced apoptosis of immature thymocytes and T-cell hybridomas. To illustrate the mechanism of the inhibition, we e xamined the effects of retinoic acid (RA) on the expression and transactiva tion functions of Nur77 in the human peripheral blood mononuclear cells and the human T-cell leukemia, Jurkat. All-trans-RA remarkably repressed the D NA binding and transcriptional induction of Nur77. Among the two potential transacting factors that activate Nur77 gene promoter, i.e., AP-1 and relat ed serum response factor (RSRF), all-trans-RA repressed DNA binding and rep orter gene activity of AP-1 but not that of RSRF, suggesting that the inhib ition may be mediated through AP-1. We also demonstrated a posttranscriptio nal regulation of Nur77 function by retinoid receptors by showing that tran sactivation activity of Nur77 was significantly inhibited by cotransfection of RAR alpha or RXR alpha. Nur77 bound RAR alpha or RXR alpha in both yeas t and mammalian two-hybrid tests, suggesting that direct protein-protein in teraction between these receptors may mediate the inhibition. Taken all tog ether, we demonstrated that RA repressed Nur77 function through multiple me chanisms that may provide the basis for RA inhibition on the apoptosis of a ctivated T-lymphocytes. (C) 2000 Academic Press.