Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation

We have recently shown that the orphan nuclear receptor Nur77 (NGFI-B) is m ost active in transcription when it is interacting with a cognate DNA seque nce as a homodimer. Further, we have shown that the target for Nur77 dimers , the Nur response element (NurRE), is responsive to physiological stimuli in both endocrine and lymphoid cells, whereas other DNA targets of Nur77 ac tion are not. The Nur77 subfamily also includes two related receptors, Nur- related factor 1 (Nurr1) and neuron-derived orphan receptor 1 (NOR-1). Ofte n, more than one member of this subfamily is induced in response to extrace llular signals. We now show that Nur77 and Nurr1 form heterodimers in vitro in the presence or absence of NurRE, and we have documented interactions b etween these proteins in vivo by using a two-hybrid system in mammalian cel ls. These heterodimers synergistically enhance transcription from NurRE rep orters in comparison to that seen with homodimers. The naturally occurring NurRE from the pro-opiomelanocortin gene preferentially binds and activates transcription in the presence of Nur77 homo- or heterodimers, while a cons ensus NurRE sequence does not show this preference. Taken together, the dat a indicate that members of the Nur77 subfamily are most potent as heterodim ers and that different dimers exhibit target sequence preference. Thus, we propose that a combinatorial code relying on specific NurRE sequences might be responsible for the activation of subsets of target genes by one of the members of the Nur77 subfamily of transcription factors.