Differential regulation of transcription by the NURR1/NUR77 subfamily of nuclear transcription factors.

NURR1 is an orphan member of the nuclear receptor superfamily of transcription factors that shares close sequence homology to the orphan nuclear receptor and immediate early gene product NUR77(NGF1 beta). The physiological role of NURR1 has not been established in mammalian cells. However, the observation that NURR1 and NUR77 interact with at least one common enhancer element (AAAAGGTCA), together with their partly overlapping but differential expression patterns in mammalian tissues, suggests that these proteins may have both shared and independent transcription regulatory functions. To identify potential target genes that may be regulated by NURR1, we analyzed its DNA binding properties to potential cis-acting enhancer elements. Using point mutagenesis of the AAAAGGTCA motif, we have identified three additional sequences that bind specifically to both NURR1 and NUR77, one of which serves as a functional enhancer element. Comparative analysis of the transcription regulatory properties of NURR1 and NUR77 indicates that the proteins can display opposing transregulatory activities that are influenced by the specific cis-acting sequences to which they bind. Our results indicate that the transcriptional responses of specific target genes to the NURR1/NUR77 subfamily may be differentially regulated by the relative cellular levels of NURR1 and NUR77 and influenced by the specific enhancer sequences that mediate their activity. Finally, we have identified several potential target genes of neuronal and neuroendocrine origin whose promoters contain this element.