Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation

Abstract

We have recently shown that the orphan nuclear receptor Nur77 (NGFI-B) is most active in transcription when it is interacting with a cognate DNA sequence 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 action are not. The Nur77 subfamily also includes two related receptors, Nur-related factor 1 (Nurr1) and neuron-derived orphan receptor 1 (NOR-1). Often, more than one member of this subfamily is induced in response to extracellular signals. We now show that Nur77 and Nurr1 form heterodimers in vitro in the presence or absence of NurRE, and we have documented interactions between these proteins in vivo by using a two-hybrid system in mammalian cells. These heterodimers synergistically enhance transcription from NurRE reporters 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 consensus NurRE sequence does not show this preference. Taken together, the data indicate that members of the Nur77 subfamily are most potent as heterodimers 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.

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

“…Additionally, RXR is highly versatile with respect to its heterodimerization; among the many other nuclear receptors with which it can interact are two members of the orphan nuclear subfamily, Nur77 and Nurr1. These factors also function independently by binding Nur‐response elements, as monomers (NBRE) and dimers (NurRE) (Maira et al, 1999; Maira et al, 2003; Lefebvre et al, 2010). nFGFR1 forms CBP‐containing low mobility chromatin complexes with RXR, RAR, and Nurs.…”

The NR4A family of orphan nuclear receptors are not required for adipogenesis

“…Nur77, Nurr1 and Nor1 exhibit redundancy in many of their reported functions. 16,17 Moreover, previous microarray analyses of nuclear hormone receptor expression have demonstrated that, like Nur77, Nurr1 and Nor1 are rapidly and transiently induced in differentiating 3T3-L1 preadipocytes, raising the possibility that they may compensate for the loss of Nur77 in our cells. To test this, we employed an N-terminally truncated dominant-negative form of Nur77, which has been extensively characterized in several studies and exerts a strong dominant-negative effect against all members of the NR4A family.…”

“…To test this, we employed an N-terminally truncated dominant-negative form of Nur77, which has been extensively characterized in several studies and exerts a strong dominant-negative effect against all members of the NR4A family. [16][17][18] Wild-type and dominantnegative Nur77 (DN-Nur77) were subcloned into the retroviral pBabe vector, retroviruses were generated and used to infect 3T3-L1 preadipocytes to produce stable cell lines. Mock-transfected cells were generated by infection with empty virus.…”

Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover

“…In addition, Nurr1 can modulate the expression of the DA transporter (DAT) and vesicular monoamine transporter (VMAT) (Hermanson et al 2003;Sacchetti et al 2001). Responsive elements sensitive to Nurr1 present in those gene promoters can also represent putative targets for other Nur members (Maira et al 1999;Perlmann and Jansson 1995). However, Nur77 (NR4A1) and Nor-1 (NR4A3) messenger RNA (mRNA) levels are extremely low in the substantia nigra (SN) and ventral tegmental area (VTA) in basal conditions (Zetterström et al 1996).…”