Nuclear receptor 4A1 explained

The nuclear receptor 4A1 (NR4A1 for "nuclear receptor subfamily 4 group A member 1") also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.

Nuclear receptor 4A1 (NR4A1) is a member of the NR4A nuclear receptor family[1] of intracellular transcription factors.[2] [3] NR4A1 is involved in cell cycle mediation, inflammation and apoptosis.

Nuclear receptor 4A1 plays a key role in mediating inflammatory responses in macrophages.[4] In addition, subcellular localization of the NR4A1 protein appears to play a key role in the survival and death of cells.[5]

Expression is inducible by phytohemagglutinin 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.[6]

Structure

The NR4A1 gene contains seven exons. An amino terminal transactivation domain is encoded in exon 2, a DNA-binding domain in exons 3 and 4, and dimerisation and a ligand-binding domain is exons 5 to 7.

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.

Cofactors interact with Nuclear receptor 4A1 at a hydrophobic region between helices 11 and 12 to modulate transcription.

Function

Along with the two other NR4A family members, NR4A1 is expressed in macrophages following inflammatory stimuli. This process is mediated by the NF-κB (nuclear factor-kappa B) complex, a ubiquitous transcription factor involved in cellular response to stress.

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". 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.[7]

There are several ligands that directly bind NR4A1, including cytosporone B, 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.[8] NR4A1 may play a role in Drug-induced gingival overgrowth associated with exposure to phenytoin, nifedipine, and cyclosporine A.[9]

Biochemistry

Nuclear receptor 4A1 binds as a monomer or homodimer to response element NBRE[10] and as a homodimer to NurRE.[11] It is also capable of heterodimerising with COUP-TF (an orphan nuclear receptor) and retinoid X receptor (RXR) in mediating transcription in response to retinoids.[12]

The binding sites on the response elements for NR4A1, which are common to the two other members of the NR4A family, are:

Evolution and homology

Nuclear receptor 4A1 has the systematic HUGO gene symbol NR4A1. It belongs to a group of three closely related orphan receptors, the NR4A family (NR4A). The other two members are Nuclear receptor 4A2 (NR4A2) and Nuclear 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% sequence conservation. 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.

The three members are similar in biochemistry and function. They are immediate early genes activated in a ligand-independent manner that bind at the homologous sites on response elements.[13]

Nuclear receptor 4A1 and the rest of the NR4A family are structurally similar to other nuclear receptor superfamily members, but contain an extra intron. The DNA-binding domain at exons 3 and 4 of the NR4A1 gene is conserved among all members of the nuclear receptor.

NR4A1 has homologous genes in a range of species including neuronal growth factor-induced clone B in rats, Nur77 in mice and TR3 in humans.[14]

Pathology

Along with 16 other genes, NR4A1 is a signature gene in the metastasis of some primary solid tumours. It is downregulated in this process.[15]

Interactions

Nuclear receptor 4A1 has been shown to interact with:

Further reading

Notes and References

  1. Maxwell MA, Muscat GE . The NR4A subgroup: immediate early response genes with pleiotropic physiological roles . Nuclear Receptor Signaling . 4 . e002 . 2006 . 16604165 . 1402209 . 10.1621/nrs.04002 .
  2. Chang C, Kokontis J, Liao SS, Chang Y . Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily . Journal of Steroid Biochemistry . 34 . 1–6 . 391–395 . 1989 . 2626032 . 10.1016/0022-4731(89)90114-3 .
  3. Milbrandt J . Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene . Neuron . 1 . 3 . 183–188 . May 1988 . 3272167 . 10.1016/0896-6273(88)90138-9 . 41639878 .
  4. Pei L, Castrillo A, Tontonoz P . Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77 . Molecular Endocrinology . 20 . 4 . 786–794 . April 2006 . 16339277 . 10.1210/me.2005-0331 . free .
  5. Zhang XK . Targeting Nur77 translocation . Expert Opinion on Therapeutic Targets . 11 . 1 . 69–79 . January 2007 . 17150035 . 10.1517/14728222.11.1.69 . 2217539 .
  6. Web site: Entrez Gene: NR4A1 nuclear receptor subfamily 4, group A, member 1.
  7. Liu X, Wang Y, Lu H, Li J, Yan X, Xiao M, Hao J, Alekseev A, Khong H, Chen T, Huang R, Wu J, Zhao Q, Wu Q, Xu S, Wang X, Jin W, Yu S, Wang Y, Wei L, Wang A, Zhong B, Ni L, Liu X, Nurieva R, Ye L, Tian Q, Bian XW, Dong C . 6 . Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction . Nature . 567 . 7749 . 525–529 . March 2019 . 30814730 . 6507425 . 10.1038/s41586-019-0979-8 . 2019Natur.567..525L .
  8. Safe S, Shrestha R, Mohankumar K . Orphan nuclear receptor 4A1 (NR4A1) and novel ligands . Essays in Biochemistry . 65 . 6 . 877–886 . December 2021 . 34096590 . 10.1042/EBC20200164 . 235360253 .
  9. Hatano S, Matsuda S, Okanobu A, Furutama D, Memida T, Kajiya M, Ouhara K, Fujita T, Mizuno N, Kurihara H . 6 . The role of nuclear receptor 4A1 (NR4A1) in drug-induced gingival overgrowth . FASEB Journal . 35 . 7 . e21693 . July 2021 . 34109683 . 10.1096/fj.202100032R . free . 235393903 .
  10. Hiromura M, Suizu F, Narita M, Kinowaki K, Noguchi M . Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element . The Journal of Biological Chemistry . 281 . 38 . 27753–27764 . September 2006 . 16835233 . 10.1074/jbc.M602420200 . free . 2115/14759 . free .
  11. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J . Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells . Molecular and Cellular Biology . 17 . 10 . 5946–5951 . October 1997 . 9315652 . 232442 . 10.1128/MCB.17.10.5946 .
  12. Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J, Reed JC, Dawson MI, Zhang XK . 6 . Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt . Oncogene . 25 . 21 . 2974–2986 . May 2006 . 16434970 . 10.1038/sj.onc.1209358 . free .
  13. Saucedo-Cardenas O, Kardon R, Ediger TR, Lydon JP, Conneely OM . Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1 . Gene . 187 . 1 . 135–139 . March 1997 . 9073077 . 10.1016/S0378-1119(96)00736-6 .
  14. Wei T, Geiser AG, Qian HR, Su C, Helvering LM, Kulkarini NH, Shou J, N'Cho M, Bryant HU, Onyia JE . 6 . DNA microarray data integration by ortholog gene analysis reveals potential molecular mechanisms of estrogen-dependent growth of human uterine fibroids . BMC Women's Health . 7 . 5 . April 2007 . 17407572 . 1852551 . 10.1186/1472-6874-7-5 . free .
  15. Ramaswamy S, Ross KN, Lander ES, Golub TR . A molecular signature of metastasis in primary solid tumors . Nature Genetics . 33 . 1 . 49–54 . January 2003 . 12469122 . 10.1038/ng1060 . 12059602 .
  16. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM . 6 . Akt phosphorylates and regulates the orphan nuclear receptor Nur77 . Proceedings of the National Academy of Sciences of the United States of America . 98 . 7 . 3690–3694 . March 2001 . 11274386 . 31113 . 10.1073/pnas.051003198 . free . 2001PNAS...98.3690P .
  17. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK . 6 . Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 . Cell . 116 . 4 . 527–540 . February 2004 . 14980220 . 10.1016/S0092-8674(04)00162-X . free .
  18. Kim BY, Kim H, Cho EJ, Youn HD . Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation . Experimental & Molecular Medicine . 40 . 1 . 71–83 . February 2008 . 18305400 . 2679322 . 10.3858/emm.2008.40.1.71 .
  19. Sohn YC, Kwak E, Na Y, Lee JW, Lee SK . Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77 . The Journal of Biological Chemistry . 276 . 47 . 43734–43739 . November 2001 . 11559707 . 10.1074/jbc.M107208200 . free .
  20. Wu WS, Xu ZX, Ran R, Meng F, Chang KS . Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions . Oncogene . 21 . 24 . 3925–3933 . May 2002 . 12032831 . 10.1038/sj.onc.1205491 . 23367035 .

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