The NR4A subgroup: immediate early response genes with pleiotropic physiological roles

Abstract

The nuclear hormone receptor (NR) superfamily includes the orphan NR4A subgroup, comprised of Nur77 (NR4A1), Nurr1 (NR4A2) and NOR-1 (NR4A3). These NRs are classified as early response genes, are induced by a diverse range of signals, including fatty acids, stress, growth factors, cytokines, peptide hormones, phorbol esters, neurotransmitters, and physical stimuli (for example magnetic fields, shear stress). The ability to sense and rapidly respond to changes in the cellular environment thus appears to be a hallmark of this subfamily. The members of the NR4A subgroup are well conserved in the DNA binding domain (approximately 91-95%) and the C-terminal ligand-binding domain (approximately 60%), but are divergent in the N-terminal AB region. These receptors bind as monomers, homodimers and heterodimers with RXRs (to mediate retinoid signaling) to different permutations of the canonical NR binding motif. The NR4A subgroup activates gene expression in a constitutive ligand-independent manner. NR4A-mediated trans-activation (LBD) involves unusually active N-terminal AF-1 domains that mediate coactivator recruitment. Moreover, the NR4A receptors encode atypical LBDs and AF-2 domains. For example, the LBDs contain no cavity due to bulky hydrophobic residue side chains, and lack the classical coactivator-binding cleft constituted by helices 3, 4 and 12. However, a hydrophobic patch exists between helices 11 and 12, that encodes a novel cofactor interface that modulates transcriptional activity. In line with the pleiotropic physiological stimuli that induce the NR4A subgroup, these orphan NRs have been implicated in cell cycle regulation (and apoptosis), neurological disease, steroidogenesis, inflammation, carcinogenesis and atherogenesis.

Figure 1. NR4A response elements.

The NR4A family members can bind as monomers to the NBRE (panel A), homodimers and NR4A heterodimers to the NurRE (panel B), or heterodimers with RXR to the DR5 motif (panel C). The naturally occurring NurRE from the pro-opiomelanocortin (POMC) promoter is shown.

Figure 2. Diverse stimuli induce the NR4A subgroup.

Nur77, NOR-1 and Nurr1, immediate early response genes that sense and respond to changes in the cellular environment, are induced by physiological and physical stimuli.

Figure 3. Organ and tissue specific effects of the NR4A subgroup.

Schematic summarising the pleiotropic, cell-specific effects of this NR subgroup, that function as immediate early response genes in a variety of pathophysiological conditions.