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 transcriptional activation of nur77, a growth factor-inducible gene encoding a member of the steroid/thyroid hormone receptor superfamily. Although initially identified as a serum-inducible immediate-early gene with expression kinetics similar to those of c-fos, we found that transcriptional activation of nur77 by serum growth factors in fibroblasts is in fact composed of two components: an immediate-early component, which can occur in the absence of de novo protein synthesis, and a delayed-early component, which is dependent on de novo protein synthesis. The expression of nur77 following serum stimulation reflects the superimposition of immediate-early and delayed-early expression. Immediate-early and delayed-early expression can be dissociated from one another by deletion or base substitution mutations of the nur77 promoter. Immediate-early expression of nur77 is mediated primarily by sequences located between nucleotides -86 and -126 upstream of the transcription start site. This region includes a sequence that resembles but differs from the CArG element found in other serum-inducible promoters. Upstream of the CArG-like element is a potential binding site for a transcription factor of the Ets family; the presence of this site is required for significant transcriptional induction. Delayed-early expression of nur77 is mediated by multiple AP-1-like and GC-rich elements, which can interact with products of immediate-early genes such as Fos/Jun and Zif268, respectively. Furthermore, we show that Zif268 can activate transcription of the nur77 promoter, suggesting that it may play a role in the delayed-early expression of nur77.