Thenuclear receptor 4A1 (NR4A1 for "nuclear receptor subfamily 4 group A member 1") also known asNur77,TR3, andNGFI-B is aprotein that in humans is encoded by theNR4A1gene.[5][6]
Nuclear receptor 4A1 plays a key role in mediatinginflammatory responses inmacrophages.[9] In addition, subcellular localization of the NR4A1 protein appears to play a key role in the survival and death of cells.[10]
Expression is inducible byphytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified.[5]
TheNR4A1 gene contains sevenexons. An amino terminaltransactivation domain is encoded in exon 2, aDNA-binding domain in exons 3 and 4, and dimerisation and a ligand-binding domain is exons 5 to 7.[11]
The protein has an atypical ligand-binding domain that is unlike the classical ligand-binding domain in most nuclear receptors. The classical domain contains a ligand-receiving pocket and co-activator site, both of which are lacking in the NR4A family. Whereas most nuclear receptors have a hydrophobic surface that results in a cleft, NR4A1 has a hydrophilic surface.[7]
Cofactors interact with Nuclear receptor 4A1 at a hydrophobic region between helices 11 and 12 to modulate transcription.[7]
Along with the two otherNR4A family members, NR4A1 is expressed in macrophages following inflammatory stimuli. This process is mediated by theNF-κB (nuclear factor-kappa B) complex, a ubiquitoustranscription factor involved in cellular response to stress.[9]
Nuclear receptor 4A1 can be induced by many physiological and physical stimuli. These include physiological stimuli such as "fatty acids, stress, prostaglandins, growth factors, calcium, inflammatory cytokines, peptide hormones, phorbol esters, and neurotransmitters" and physical stimuli including "magnetic fields, mechanical agitation (causing fluid shear stress), and membrane depolarization".[7] No endogenous ligands that bind to NR4A1 have yet been identified, so modulation occurs at the level of protein expression and posttranslational modification.Besides these, NR4A1 can mediate T cell function, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression ofNuclear receptor 4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumor and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes.[12]
There are several ligands that directly bind NR4A1, includingcytosporone B,dexamethasone,celastrol, and certain polyunsaturated fatty acids. These NR4A1 ligands bind at various NR4A1 sites and show activities that are dependent on ligand structure and cell context. These NR4A1 ligands may have relevance to treatment of cancer, metabolic disease, inflammation, and endometriosis.[13] NR4A1 may play a role inDrug-induced gingival overgrowth associated with exposure to phenytoin, nifedipine, and cyclosporine A.[14]
Nuclear receptor 4A1 has the systematicHUGO gene symbolNR4A1. It belongs to a group of three closely related orphan receptors, theNR4A family (NR4A). The other two members areNuclear receptor 4A2 (NR4A2) andNuclear receptor 4A3 (NR4A3).
Nuclear receptor 4A1 has a high degree of structural similarity with other family members at the DNA-binding domain with 91-95% sequenceconservation. The C-terminal ligand-binding domain is conserved to a lesser extent at 60% and the N-terminal AB region is not conserved, differing in each member.[7]
The three members are similar in biochemistry and function. They areimmediate early genes activated in a ligand-independent manner that bind at the homologous sites on response elements.[11]
Nuclear receptor 4A1 and the rest of the NR4A family are structurally similar to othernuclear receptor superfamily members, but contain an extraintron. The DNA-binding domain at exons 3 and 4 of theNR4A1 gene is conserved among all members of the nuclear receptor.[11]
NR4A1 hashomologous genes in a range of species including neuronal growth factor-induced clone B inrats, Nur77 inmice and TR3 inhumans.[18]
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