ACTIVATION OF THE INDUCIBLE ORPHAN RECEPTOR GENE NUR77 BY SERUM GROWTH-FACTORS - DISSOCIATION OF IMMEDIATE-EARLY AND DELAYED-EARLY RESPONSES

We have characterized the genetic elements that mediate the transcript ional activation of nur77, a growth factor-inducible gene encoding a m ember of the steroid/thyroid hormone receptor superfamily. Although in itially identified as a serum-inducible immediate-early gene with expr ession kinetics similar to those of c-fos, we found that transcription al activation of nur77 by serum growth factors in fibroblasts is in fa ct composed of two components: an immediate-early component, which can occur in the absence of de novo protein synthesis, and a delayed-earl y component, which is dependent on de novo protein synthesis. The expr ession of nur77 following serum stimulation reflects the superimpositi on of immediate-early and delayed-early expression. Immediate-early an d delayed-early expression can be dissociated from one another by dele tion or base substitution mutations of the nur77 promoter. Immediate-e arly expression of nur77 is mediated primarily by sequences located be tween nucleotides -86 and -126 upstream of the transcription start sit e. This region includes a sequence that resembles but differs from the CArG element found in other serum-inducible promoters. Upstream of th e CArG-like element is a potential binding site for a transcription fa ctor of the Ets family; the presence of this site is required for sign ificant transcriptional induction. Delayed-early expression of nur77 i s mediated by multiple A-P-1-like and GC-rich elements, which can inte ract with products of immediate-early genes such as Fos/Jun and Zif268 , respectively. Furthermore, we show that Zif268 can activate transcri ption of the nur77 promoter, suggesting that it may play a role in the delayed-early expression of nur77.