NOVEL MECHANISM OF ACTION FOR NUR77 AND ANTAGONISM BY GLUCOCORTICOIDS- A CONVERGENT MECHANISM FOR CRH ACTIVATION AND GLUCOCORTICOID REPRESSION OF POMC GENE-TRANSCRIPTION

Whereas orphan nuclear receptors of the Nur77 (NGFI-B) subfamily were previously known to act on transcription as monomers or as heterodimer s with RXR, we have recently shown that Nur77 homodimers potently acti vate transcription upon interaction with a novel palindromic response element, the NurRE. In fact, reporter plasmids containing the NurRE re spond to physiological stimuli in conditions where the NBRE, a binding site for Nur77 monomers, does not. Nur77 and its related receptors we re shown to be important mediators for control of apoptosis induced by the T-cell receptor, and they also mediate the effect of the hypothal amic hormone CRH on transcription of the pituitary pro-opiomelanocotin (POMC) gene. In both systems, glucocorticoids antagonize the stimulat ory effects of Nur77 on transcription by a mechanism that involves pro tein:protein interactions. Thus, the Nur77 signalling pathway appears to be a point of convergence for stimulatory signals and glucocorticoi d repression in both endocrine and lymphoid systems. (C) 1998 Elsevier Science Ltd. All rights reserved.