TRANSCRIPTIONAL ACTIVATION OF THE INDUCIBLE NUCLEAR RECEPTOR GENE NUR77 BY NERVE GROWTH-FACTOR AND MEMBRANE DEPOLARIZATION IN PC12 CELLS

nur77 is an immediate-early gene inducible by nerve growth factor or m embrane depolarization in the rat pheochromocytoma cell line PC12 and by serum growth factors in fibroblasts. The nur77-encoded protein is a member of the steroid/thyroid hormone receptor superfamily and can ac t as a potent transcription activator. The induction of nur77 in PC12 cells is rapid and transient, with kinetics similar to those of the c- fos protooncogene. Induction does not require de novo protein synthesi s. Whereas transcriptional activation of c-fos by nerve growth factor in PC12 cells requires a 20-base pair serum response element in its pr omoter, there is no such sequence in the nur77 promoter. To understand the mechanism for the activation of nur77, we have analyzed the induc ibility of a series of transfected nur77 minigenes using an S1 nucleas e protection assay. We identified the sequence 22-86 nucleotides upstr eam of the transcription start site as necessary and sufficient for nu r77 induction by nerve growth factor and membrane depolarization in PC 12 cells. Sequences farther upstream enhance the induction. Analysis o f base substitution mutations allowed us to identify three sequence el ements within this region that are essential for induction. These sequ ence elements include two copies of an AP1-like element and a GC-rich sequence. Unlike transcriptional activation of c-fos, the sequence req uirements for the activation of nur77 by nerve growth factor and membr ane depolarization cannot be readily separated. Taken together, our da ta suggest that activation of nur77 and c-fos by nerve growth factor o ccurs through different mechanisms in PC12 cells.