Biology:Nerve growth factor IB

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The nerve growth factor IB (NGFIB) also known as Nur77 or NR4A1 (nuclear receptor subfamily 4 group A member 1) is a protein that in humans is encoded by the NR4A1 gene.[1][2]

Nerve growth factor IB is a member of the Nur nuclear receptor family[3] of intracellular transcription factors.[2][4] NGFIB is involved in cell cycle mediation, inflammation and apoptosis.[5]

The NGFIB protein plays a key role in mediating inflammatory responses in macrophages.[5] In addition, subcellular localization of the NGFIB protein appears to play a key role in the survival and death of cells.[6]

Expression is induced 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.[1]

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 ligand-binding domains is exons 5 to 7.[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, NGFI-B has a hydrophilic surface.[3]

Cofactors interact with NGFI-B at a hydrophobic region between helices 11 and 12 to modulate transcription.[3]

Function

Along with the two other Nur family members, NGFIB 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.[5]

NGFIB 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".[3] Ligands do not bind to NGFIB, so modulation occurs at the level of protein expression and posttranslational modification.[5] Besides these, NR4A1 can mediate T cell function, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 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.[8]

Biochemistry

Nerve growth factor IB binds as a monomer or homodimer to response element NBRE[9] and as a homodimer to NurRE.[10] 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.[11]

The binding sites on the response elements for NGFI-B, which are common to the two other members of the Nur family, are:[3]

  • NBRE - 5’-A/TAAAGGTCA,
  • NurRE - a AAAT(G/A)(C/T)CA repeat,
  • RXR - DX, a motif.

Evolution and homology

Nerve growth factor IB has the systematic HUGO gene symbol NR4A1. It belongs to a group of three closely related orphan receptors, the Nur family, which has the symbol NR4A. The other two members are nuclear receptor related 1 protein (denoted by symbol NR4A2) and neuron-derived orphan receptor 1 (NR4A3).

NGFIB 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.[3]

The three members are similar in biochemistry and function. They are immediate early genes activated in a ligand-independent manner that bind at the same sites on response elements.[7]

NGFIB and the rest of the Nur 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.[7]

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.[12]

Pathology

Along with 16 other genes, Nerve growth factor IB is a signature gene in the metastasis of some primary solid tumours. It is downregulated in this process.[13]

Interactions

Nerve growth factor IB has been shown to interact with:


References

  1. ↑ 1.0 1.1 "Entrez Gene: NR4A1 nuclear receptor subfamily 4, group A, member 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3164. 
  2. ↑ 2.0 2.1 "Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily". J. Steroid Biochem. 34 (1–6): 391–5. 1989. doi:10.1016/0022-4731(89)90114-3. PMID 2626032. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "The NR4A subgroup: immediate early response genes with pleiotropic physiological roles". Nucl Recept Signal 4: e002. 2006. doi:10.1621/nrs.04002. PMID 16604165. 
  4. ↑ Milbrandt J (1988). "Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene". Neuron 1 (3): 183–8. doi:10.1016/0896-6273(88)90138-9. PMID 3272167. 
  5. ↑ 5.0 5.1 5.2 5.3 "Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77". Mol. Endocrinol. 20 (4): 786–94. 2006. doi:10.1210/me.2005-0331. PMID 16339277. 
  6. ↑ Zhang XK (2007). "Targeting Nur77 translocation". Expert Opin. Ther. Targets 11 (1): 69–79. doi:10.1517/14728222.11.1.69. PMID 17150035. 
  7. ↑ 7.0 7.1 7.2 "Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1". Gene 187 (1): 135–9. 1997. doi:10.1016/S0378-1119(96)00736-6. PMID 9073077. 
  8. ↑ "Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction". Nature 567 (7749): 525–529. March 2019. doi:10.1038/s41586-019-0979-8. PMID 30814730. 
  9. ↑ "Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element". J. Biol. Chem. 281 (38): 27753–64. 2006. doi:10.1074/jbc.M602420200. PMID 16835233. 
  10. ↑ "Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells". Mol. Cell. Biol. 17 (10): 5946–51. 1997. doi:10.1128/MCB.17.10.5946. PMID 9315652. 
  11. ↑ "Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt". Oncogene 25 (21): 2974–86. 2006. doi:10.1038/sj.onc.1209358. PMID 16434970. 
  12. ↑ "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. 2007. doi:10.1186/1472-6874-7-5. PMID 17407572. 
  13. ↑ "A molecular signature of metastasis in primary solid tumors". Nat. Genet. 33 (1): 49–54. 2003. doi:10.1038/ng1060. PMID 12469122. 
  14. ↑ "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3690–4. March 2001. doi:10.1073/pnas.051003198. PMID 11274386. 
  15. ↑ 15.0 15.1 "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell 116 (4): 527–40. February 2004. doi:10.1016/S0092-8674(04)00162-X. PMID 14980220. 
  16. ↑ 16.0 16.1 "Nur77 upregulates HIF-α by inhibiting pVHL-mediated degradation". Experimental & Molecular Medicine 40 (1): 71–83. February 2008. doi:10.3858/emm.2008.40.1.71. PMID 18305400. 
  17. ↑ "Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77". J. Biol. Chem. 276 (47): 43734–9. November 2001. doi:10.1074/jbc.M107208200. PMID 11559707. 
  18. ↑ "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions". Oncogene 21 (24): 3925–33. May 2002. doi:10.1038/sj.onc.1205491. PMID 12032831. 

Further reading

External links




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