Nerve Growth factor IB: Wikis

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Nuclear receptor subfamily 4, group A, member 1

PDB rendering based on 1cit.
Available structures
1cit, 1yje, 2gbd
Identifiers
Symbols NR4A1; GFRP1; HMR; MGC9485; N10; NAK-1; NGFIB; NP10; NUR77; TR3; DHR38; TIS1
External IDs OMIM139139 MGI1352454 HomoloGene1612 GeneCards: NR4A1 Gene
RNA expression pattern
PBB GE NR4A1 202340 x at tn.png
PBB GE NR4A1 210226 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3164 15370
Ensembl ENSG00000123358 ENSMUSG00000023034
UniProt P22736 Q545Q1
RefSeq (mRNA) NM_002135 NM_010444
RefSeq (protein) NP_002126 NP_034574
Location (UCSC) Chr 12:
50.72 - 50.74 Mb
Chr 15:
101.09 - 101.1 Mb
PubMed search [1] [2]

The Nerve Growth factor IB (NGFIB, also known as Nur77) protein is a member of the Nur nuclear receptor family[1] of intracellular transcription factors and is encoded by the NR4A1 gene (nuclear receptor subfamily 4, group A, member 1).[2][3] NGFIB is involved in cell cycle mediation, inflammation and apoptosis.[4]

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

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.[6]

Contents

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. Where most nuclear receptors have a hydrophobic surface that results in a cleft, NGFI-B has a hydrophilic surface.[1]

Cofactors interact with NGFI-B at a hydrophobic region between helices 11 and 12 to modulate transcription.[1]

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.[4]

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".[1] Ligands do not bind to NGFIB, so modulation occurs at the level of protein expression and posttranslational modification.[4]

Biochemistry

Nerve Growth factor IB binds as a monomer or homodimer to response element NBRE[8] and as a homodimer to NurRE.[9] 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.[10]

The binding sites on the response elements for NGFI-B, which are common to the two other members of the Nur family, are [1]:

  • 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.[1]

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.[11]

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.[12]

Interactions

Nerve Growth factor IB has been shown to interact with HIF1A,[13] Bcl-2,[14] Nuclear receptor co-repressor 2,[15] AKT1,[16] Promyelocytic leukemia protein,[17] Von Hippel-Lindau tumor suppressor[13] and Retinoid X receptor alpha.[14]

References

  1. ^ a b c d e f Maxwell MA, Muscat GE (2006). "The NR4A subgroup: immediate early response genes with pleiotropic physiological roles". Nucl Recept Signal 4: e002. doi:10.1621/nrs.04002. PMID 16604165.  
  2. ^ 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.  
  3. ^ Chang C, Kokontis J, Liao SS, Chang Y (1989). "Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily". J. Steroid Biochem. 34 (1-6): 391–5. doi:10.1016/0022-4731(89)90114-3. PMID 2626032.  
  4. ^ a b c d Pei L, Castrillo A, Tontonoz P (2006). "Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77". Mol. Endocrinol. 20 (4): 786–94. doi:10.1210/me.2005-0331. PMID 16339277.  
  5. ^ Zhang XK (2007). "Targeting Nur77 translocation". Expert Opin. Ther. Targets 11 (1): 69–79. doi:10.1517/14728222.11.1.69. PMID 17150035.  
  6. ^ "Entrez Gene: NR4A1 nuclear receptor subfamily 4, group A, member 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3164.  
  7. ^ a b c Saucedo-Cardenas, O; R Kardon, T R Ediger, J P Lydon, O M Conneely (1997-03-10). "Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1". Gene 187 (1): 135–9. doi:10.1016/S0378-1119(96)00736-6. ISSN 03781119. PMID 9073077.  
  8. ^ Hiromura M, Suizu F, Narita M, Kinowaki K, Noguchi M (2006). "Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element". J. Biol. Chem. 281 (38): 27753–64. doi:10.1074/jbc.M602420200. PMID 16835233.  
  9. ^ Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J (1997). "Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells". Mol. Cell. Biol. 17 (10): 5946–51. PMID 9315652. http://mcb.asm.org/cgi/content/abstract/17/10/5946.  
  10. ^ Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J, Reed JC, Dawson MI, Zhang XK (2006). "Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt". Oncogene 25 (21): 2974–86. doi:10.1038/sj.onc.1209358. PMID 16434970.  
  11. ^ Wei, Tao; Andrew Geiser, Hui-Rong Qian, Chen Su, Leah Helvering, Nalini Kulkarini, Jianyong Shou, Mathias N'Cho, Henry Bryant, Jude Onyia (2007). "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 (1): 5. doi:10.1186/1472-6874-7-5. ISSN 1472-6874. PMID 17407572. http://www.biomedcentral.com/1472-6874/7/5. Retrieved 2007-12-20.  
  12. ^ Ramaswamy S, Ross KN, Lander ES, Golub TR (2003). "A molecular signature of metastasis in primary solid tumors". Nat. Genet. 33 (1): 49–54. doi:10.1038/ng1060. PMID 12469122.  
  13. ^ a b Kim, Bu Yeon; Kim Hyungsoo, Cho Eun Jung, Youn Hong Duk (Feb. 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Exp. Mol. Med. (Korea (South)) 40 (1): 71–83. ISSN 1226-3613. PMID 18305400.  
  14. ^ a b Lin, Bingzhen; Kolluri Siva Kumar, Lin Feng, Liu Wen, Han Young-Hoon, Cao Xihua, Dawson Marcia I, Reed John C, Zhang Xiao-kun (Feb. 2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell (United States) 116 (4): 527–40. ISSN 0092-8674. PMID 14980220.  
  15. ^ Sohn, Y C; Kwak E, Na Y, Lee J W, Lee S K (Nov. 2001). "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. (United States) 276 (47): 43734–9. doi:10.1074/jbc.M107208200. ISSN 0021-9258. PMID 11559707.  
  16. ^ Pekarsky, Y; Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce C M (Mar. 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (7): 3690–4. doi:10.1073/pnas.051003198. ISSN 0027-8424. PMID 11274386.  
  17. ^ Wu, Wen-Shu; Xu Zhi-Xiang, Ran Ruixiang, Meng Feng, Chang Kun-Sang (May. 2002). "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions". Oncogene (England) 21 (24): 3925–33. doi:10.1038/sj.onc.1205491. ISSN 0950-9232. PMID 12032831.  

Further reading

  • Winoto A, Littman DR (2002). "Nuclear hormone receptors in T lymphocytes.". Cell 109 Suppl: S57–66. doi:10.1016/S0092-8674(02)00710-9. PMID 11983153.  
  • Engelse MA, Arkenbout EK, Pannekoek H, de Vries CJ (2004). "Activin and TR3 orphan receptor: two 'atheroprotective' genes as evidenced in dedicated mouse models.". Clin. Exp. Pharmacol. Physiol. 30 (11): 894–9. doi:10.1046/j.1440-1681.2003.03928.x. PMID 14678255.  
  • Bondy GP (1991). "Phorbol ester, forskolin, and serum induction of a human colon nuclear hormone receptor gene related to the NUR 77/NGFI-B genes.". Cell Growth Differ. 2 (4): 203–8. PMID 1651101.  
  • Nakai A, Kartha S, Sakurai A, et al. (1991). "A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily.". Mol. Endocrinol. 4 (10): 1438–43. doi:10.1210/mend-4-10-1438. PMID 2283997.  
  • Ryseck RP, Macdonald-Bravo H, Mattéi MG, et al. (1989). "Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor.". EMBO J. 8 (11): 3327–35. PMID 2555161.  
  • Chang C, Kokontis J, Liao SS, Chang Y (1990). "Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily.". J. Steroid Biochem. 34 (1-6): 391–5. doi:10.1016/0022-4731(89)90114-3. PMID 2626032.  
  • Uemura H, Mizokami A, Chang C (1995). "Identification of a new enhancer in the promoter region of human TR3 orphan receptor gene. A member of steroid receptor superfamily.". J. Biol. Chem. 270 (10): 5427–33. doi:10.1074/jbc.270.10.5427. PMID 7890657.  
  • Hirata Y, Kiuchi K, Chen HC, et al. (1993). "The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B.". J. Biol. Chem. 268 (33): 24808–12. PMID 8227042.  
  • Harrison DC, Roberts J, Campbell CA, et al. (2000). "TR3 death receptor expression in the normal and ischaemic brain.". Neuroscience 96 (1): 147–60. doi:10.1016/S0306-4522(99)00502-3. PMID 10777386.  
  • Li H, Kolluri SK, Gu J, et al. (2000). "Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3.". Science 289 (5482): 1159–64. doi:10.1126/science.289.5482.1159. PMID 10947977.  
  • Pekarsky Y, Hallas C, Palamarchuk A, et al. (2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77.". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3690–4. doi:10.1073/pnas.051003198. PMID 11274386.  
  • Sohn YC, Kwak E, Na Y, et al. (2001). "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. doi:10.1074/jbc.M107208200. PMID 11559707.  
  • Lee MO, Kang HJ, Cho H, et al. (2001). "Hepatitis B virus X protein induced expression of the Nur77 gene.". Biochem. Biophys. Res. Commun. 288 (5): 1162–8. doi:10.1006/bbrc.2001.5910. PMID 11700033.  
  • Slagsvold HH, Østvold AC, Fallgren AB, Paulsen RE (2002). "Nuclear receptor and apoptosis initiator NGFI-B is a substrate for kinase ERK2.". Biochem. Biophys. Res. Commun. 291 (5): 1146–50. doi:10.1006/bbrc.2002.6579. PMID 11883936.  
  • Wu WS, Xu ZX, Ran R, et al. (2002). "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions.". Oncogene 21 (24): 3925–33. doi:10.1038/sj.onc.1205491. PMID 12032831.  
  • Liu S, Wu Q, Ye XF, et al. (2002). "Induction of apoptosis by TPA and VP-16 is through translocation of TR3.". World J. Gastroenterol. 8 (3): 446–50. PMID 12046067.  
  • Wansa KD, Harris JM, Muscat GE (2002). "The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment.". J. Biol. Chem. 277 (36): 33001–11. doi:10.1074/jbc.M203572200. PMID 12082103.  
  • Chtarbova S, Nimmrich I, Erdmann S, et al. (2002). "Murine Nr4a1 and Herpud1 are up-regulated by Wnt-1, but the homologous human genes are independent from beta-catenin activation.". Biochem. J. 367 (Pt 3): 723–8. doi:10.1042/BJ20020699. PMID 12153396.  
  • Wu Q, Liu S, Ye XF, et al. (2002). "Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells.". Carcinogenesis 23 (10): 1583–92. doi:10.1093/carcin/23.10.1583. PMID 12376465.  

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