Retinoid X receptor alpha explained

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 (nuclear receptor subfamily 2, group B, member 1) is a nuclear receptor that in humans is encoded by the RXRA gene.^[1]

Function

Retinoid X receptors (RXRs) and retinoic acid receptors (RARs), are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. These receptors exert their action by binding, as homodimers or heterodimers, to specific sequences in the promoters of target genes and regulating their transcription. The protein encoded by this gene is a member of the steroid and thyroid hormone receptor superfamily of transcription factors.^[2] In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the cytochrome P450 system genes.^[3]

Interactive pathway map

Interactions

Retinoid X receptor alpha has been shown to interact with:

• BCL3,^[4]
• BRD8,^[5]
• CLOCK,^[6]
• FXR
• IGFBP3,^[7]
• ITGB3BP,^[8]
• LXR-β,^[9]
• MyoD,^[10]
• NCOA6,^{[11] [12] [13] [14]}
• NFKBIB,^[15]
• NPAS2,^[6]
• NRIP1,^{[16] [17]}
• NR4A1,^[18]
• NCOA2,^[19]
• NCOA3,^[20]
• POU2F1,^{[21] [22]}
• PPARGC1A,^[23]
• PPAR-γ,^{[24] [25] [26]}
• RNF8,^[27]
• RAR-α,^{[28] [29]}
• SHP,^{[30] [31]}
• TADA3L,^[32]
• TBP,^[33]
• TRIM24,^{[34] [35]}
• TR-β,^{[36] [37]} and
• VDR.^{[19] [38]}

See also

• Retinoid X receptor

Further reading

• Szanto A, Narkar V, Shen Q, Uray IP, Davies PJ, Nagy L . Retinoid X receptors: X-ploring their (patho)physiological functions . Cell Death Differ. . 11 . S126–43 . December 2004 . Suppl 2 . 15608692 . 10.1038/sj.cdd.4401533 . free .
• Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C . 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor . Cell . 68 . 2 . 397–406 . January 1992 . 1310260 . 10.1016/0092-8674(92)90479-V . 39338234 .
• Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM . Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling . Nature . 355 . 6359 . 446–9 . January 1992 . 1310351 . 6159885 . 10.1038/355446a0 . 1992Natur.355..446K .
• Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, Evans RM . Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling . Proc. Natl. Acad. Sci. U.S.A. . 89 . 4 . 1448–52 . February 1992 . 1311101 . 48468 . 10.1073/pnas.89.4.1448 . 1992PNAS...89.1448K . free .
• Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG . RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors . EMBO J. . 11 . 4 . 1409–18 . April 1992 . 1314167 . 556590 . 10.1002/j.1460-2075.1992.tb05186.x.
• Berrodin TJ, Marks MS, Ozato K, Linney E, Lazar MA . Heterodimerization among thyroid hormone receptor, retinoic acid receptor, retinoid X receptor, chicken ovalbumin upstream promoter transcription factor, and an endogenous liver protein . Mol. Endocrinol. . 6 . 9 . 1468–78 . September 1992 . 10.1210/mend.6.9.1331778 . 1331778 . 24291055 . free .
• Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U, Ong ES, Evans RM . A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR . Cell . 66 . 3 . 555–61 . August 1991 . 1651173 . 10.1016/0092-8674(81)90018-0 . 13444623 .
• Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM . Nuclear receptor that identifies a novel retinoic acid response pathway . Nature . 345 . 6272 . 224–9 . May 1990 . 2159111 . 10.1038/345224a0 . 1990Natur.345..224M . 4232833 .
• Ming-Jer Tsai . Oñate SA, Tsai SY, Tsai MJ, O'Malley BW . Sequence and characterization of a coactivator for the steroid hormone receptor superfamily . Science . 270 . 5240 . 1354–7 . 1995 . 7481822 . 10.1126/science.270.5240.1354 . 1995Sci...270.1354O . 28749162 .
• Chen JD, Evans RM . A transcriptional co-repressor that interacts with nuclear hormone receptors . Nature . 377 . 6548 . 454–7 . 1995 . 7566127 . 10.1038/377454a0 . 1995Natur.377..454C . 4361329 .
• Schulman IG, Chakravarti D, Juguilon H, Romo A, Evans RM . Interactions between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation . Proc. Natl. Acad. Sci. U.S.A. . 92 . 18 . 8288–92 . August 1995 . 7667283 . 41142 . 10.1073/pnas.92.18.8288 . 1995PNAS...92.8288S . free .
• Perlmann T, Jansson L . A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1 . Genes Dev. . 9 . 7 . 769–82 . April 1995 . 7705655 . 10.1101/gad.9.7.769 . free .
• Rastinejad F, Perlmann T, Evans RM, Sigler PB . Structural determinants of nuclear receptor assembly on DNA direct repeats . Nature . 375 . 6528 . 203–11 . 1995 . 7746322 . 10.1038/375203a0 . 1995Natur.375..203R . 4373097 .
• Forman BM, Umesono K, Chen J, Evans RM . Unique response pathways are established by allosteric interactions among nuclear hormone receptors . Cell . 81 . 4 . 541–50 . 1995 . 7758108 . 10.1016/0092-8674(95)90075-6 . 3203590 . free .
• Seol W, Choi HS, Moore DD . Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors . Mol. Endocrinol. . 9 . 1 . 72–85 . 1995 . 7760852 . 10.1210/mend.9.1.7760852 . free .
• Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D . Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha . Nature . 375 . 6530 . 377–82 . June 1995 . 7760929 . 10.1038/375377a0 . 1995Natur.375..377B . 4371873 .
• Lee JW, Choi HS, Gyuris J, Brent R, Moore DD . Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor . Mol. Endocrinol. . 9 . 2 . 243–54 . February 1995 . 10.1210/mend.9.2.7776974 . 7776974 . free .
• Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, Tempst P, Spiegelman BM . Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha . Nucleic Acids Res. . 22 . 25 . 5628–34 . December 1994 . 7838715 . 310126 . 10.1093/nar/22.25.5628 .
• Lee JW, Ryan F, Swaffield JC, Johnston SA, Moore DD . Interaction of thyroid-hormone receptor with a conserved transcriptional mediator . Nature . 374 . 6517 . 91–4 . March 1995 . 7870181 . 10.1038/374091a0 . 1995Natur.374...91L . 4324595 .
• Lee MS, Sem DS, Kliewer SA, Provencal J, Evans RM, Wright PE . NMR assignments and secondary structure of the retinoid X receptor alpha DNA-binding domain. Evidence for the novel C-terminal helix . Eur. J. Biochem. . 224 . 2 . 639–50 . September 1994 . 7925381 . 10.1111/j.1432-1033.1994.00639.x . free .

Notes and References

1. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM . Nuclear receptor that identifies a novel retinoic acid response pathway . Nature . 345 . 6272 . 224–9 . May 1990 . 2159111 . 10.1038/345224a0 . 1990Natur.345..224M . 4232833 .
2. Web site: Entrez Gene: RXRA retinoid X receptor, alpha.
3. Web site: Retinoic acid receptor RXR-alpha - Homo sapiens (Human) . UniProt .
4. Na SY, Choi HS, Kim JW, Na DS, Lee JW . Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor . J. Biol. Chem. . 273 . 47 . 30933–8 . 1998 . 9812988 . 10.1074/jbc.273.47.30933 . free .
5. Monden T, Kishi M, Hosoya T, Satoh T, Wondisford FE, Hollenberg AN, Yamada M, Mori M . p120 acts as a specific coactivator for 9-cis-retinoic acid receptor (RXR) on peroxisome proliferator-activated receptor-gamma/RXR heterodimers . Mol. Endocrinol. . 13 . 10 . 1695–703 . 1999 . 10.1210/mend.13.10.0353 . 10517671 . 25098867 . free .
6. McNamara P, Seo SB, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA . Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock . Cell . 105 . 7 . 877–89 . 2001 . 11439184 . 10.1016/S0092-8674(01)00401-9 . 6251321 . free .
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9. Seol W, Choi HS, Moore DD . Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors . Mol. Endocrinol. . 9 . 1 . 72–85 . 1995 . 7760852 . 10.1210/mend.9.1.7760852 . free .
10. Froeschlé A, Alric S, Kitzmann M, Carnac G, Auradé F, Rochette-Egly C, Bonnieu A . Retinoic acid receptors and muscle b-HLH proteins: partners in retinoid-induced myogenesis . Oncogene . 16 . 26 . 3369–78 . 1998 . 9692544 . 10.1038/sj.onc.1201894 . 6667231 .
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22. Kakizawa T, Miyamoto T, Ichikawa K, Kaneko A, Suzuki S, Hara M, Nagasawa T, Takeda T, ((Mori Ji)), Kumagai M, Hashizume K . Functional interaction between Oct-1 and retinoid X receptor . J. Biol. Chem. . 274 . 27 . 19103–8 . 1999 . 10383413 . 10.1074/jbc.274.27.19103 . free .
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24. Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, Tempst P, Spiegelman BM . Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha . Nucleic Acids Res. . 22 . 25 . 5628–34 . 1994 . 7838715 . 310126 . 10.1093/nar/22.25.5628 .
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27. Takano Y, Adachi S, Okuno M, Muto Y, Yoshioka T, Matsushima-Nishiwaki R, Tsurumi H, Ito K, Friedman SL, Moriwaki H, Kojima S, Okano Y . The RING finger protein, RNF8, interacts with retinoid X receptor alpha and enhances its transcription-stimulating activity . J. Biol. Chem. . 279 . 18 . 18926–34 . 2004 . 14981089 . 10.1074/jbc.M309148200 . free .
28. Benkoussa M, Brand C, Delmotte MH, Formstecher P, Lefebvre P . Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter . Mol. Cell. Biol. . 22 . 13 . 4522–34 . 2002 . 12052862 . 133906 . 10.1128/MCB.22.13.4522-4534.2002 .
29. Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG . RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors . EMBO J. . 11 . 4 . 1409–18 . 1992 . 1314167 . 556590 . 10.1002/j.1460-2075.1992.tb05186.x.
30. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD . The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression . Mol. Cell. Biol. . 20 . 1 . 187–95 . 2000 . 10594021 . 85074 . 10.1128/MCB.20.1.187-195.2000 .
31. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity . Mol. Endocrinol. . 16 . 9 . 2065–76 . 2002 . 12198243 . 10.1210/me.2001-0194 . free .
32. Zeng M, Kumar A, Meng G, Gao Q, Dimri G, Wazer D, Band H, Band V . Human papilloma virus 16 E6 oncoprotein inhibits retinoic X receptor-mediated transactivation by targeting human ADA3 coactivator . J. Biol. Chem. . 277 . 47 . 45611–8 . 2002 . 12235159 . 10.1074/jbc.M208447200 . free .
33. Schulman IG, Chakravarti D, Juguilon H, Romo A, Evans RM . Interactions between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation . Proc. Natl. Acad. Sci. U.S.A. . 92 . 18 . 8288–92 . 1995 . 7667283 . 41142 . 10.1073/pnas.92.18.8288 . 1995PNAS...92.8288S . free .
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