NR4A Orphan Nuclear Receptors

Abstract

Abstract-Members of the nuclear hormone receptor superfamily, including the peroxisome proliferator-activated receptor and the liver X receptor subfamilies, orchestrate transcriptional networks involved in the control of metabolism and the development of vascular disease. In addition to these well-characterized ligand-activated transcription factors, the nuclear receptor (NR) superfamily comprises many orphan receptors, whose ligands and physiological functions remain unknown. Among this group of orphan receptors is the NR4A subfamily, including Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These orphan NRs constitute an evolutionary ancient and highly conserved group of transcription factors. In contrast to other members of the superfamily, NR4A receptors function as ligand-independent transcription factors and immediate-or early-response genes, which are rapidly induced by a pleiotropy of environmental cues. Early functional studies have pointed to a critical role of NR4A receptors in regulating differentiation, proliferation, and apoptosis. More recent research has characterized NR4A receptors as key transcriptional regulators of glucose and lipid homeostasis, adipogenesis, inflammation, and vascular remodeling. In this review, we will summarize recent advances in understanding the molecular biology and physiological functions of NR4A receptors and discuss their role in the transcriptional control of metabolism and vascular remodeling.

Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells

“…As ligand-independent and constitutively active receptors, activity of the NR4A1-3 transcription factors is tightly controlled at the level of expression, nuclear localization, coactivator/corepressor recruitment, and posttranslational modifications (11,14). Enhanced NR4A activity is not only controlled by NF-kB activity but NR4A receptors have been shown to modulate NF-kB functions downstream of LPS/TLR4 and TNF-a signaling in a dynamic fashion, either repressing or enhancing NF-kB target gene expression in monocyte/macrophage cells (13, 40, 45, 46).…”

“…The NR4A1-3 orphan nuclear receptors are a subfamily of early response regulators that have emerged as key regulators of inflammatory processes required in inflammatory disease initiation and progression, controlling the magnitude of the inflammatory response (11)(12)(13)(14)(15)(16)(17). The NR4A family member, NR4A1, is pivotal in monocyte cell differentiation, polarization, and T cell homeostasis (15)(16)(17)(18).…”

Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer

“…These members are thought to act as constitutively active transcription factors that bind the promoter of target genes on consensus NBRE (AAAGGTCA) sites. Only a few direct target genes, such as vascular endothelial growth factor (VEGF)-A, have been identified to date (Pols et al, 2007;Zhao and Bruemmer, 2010;Zeng et al, 2006). Specific ligands for the NR4A family of transcription factors have not been identified, classifying them as orphan nuclear receptors (Bonta et al, 2006).…”

Nuclear Import and Export Signals Control the Subcellular Localization of Nurr1 Protein in Response to Oxidative Stress*

“…Transcription factor Nurr1 (NOT/NR4A2) together with Nur77 (NGIF-B/NR4A1) and Nor-1 (MINOR/NR4A3) constitute the orphan receptor subfamily of the steroid nuclear hormone receptors (1). These three receptors trans-activate target genes through monomer binding to a consensus nerve growth factor-responsive element (NBRE) 4 sequence (AAAGGTCA) or homodimer binding to the palindromic NurRE sequence (AAAT(G/A)(C/T)CA) (2,3).…”