TABLE 1

RARα

Receptor Nomenclature NR1B1
Receptor code 4.10.1:RA:1:B1
Molecular information Hs: 462aa, P10276, chr. 17q21.11,2
Rn: 459aa, chr. 101,3
Mm: 462aa, P11416, 11 D1,4–6
DNA binding
   Structure Heterodimer, RXR partner
   HRE core sequence PuG(G/T)TCA (DR1, DR2, DR5)
Partners Cyclin H/cdk7/TFIIH (physical functional): TFIIH phosphorylates RARα1 in its A/B region (Ser77) by cdk7 subunit7–9; AP-1 (physical, functional): RAR inhibits AP-1-driven transactivation, and AP-1 represses RAR-mediated transcription10–14; CRABPII (physical, functional): can enhance the transactivation by RARα-RXR on DR5 element15; PARP-1 (physical, functional): indispensable to RARα-mediated transcription from the RAR α216
Agonists 9-cis-Retinoic acid (0.3 nM),* all-trans-retinoic acid (0.4 nM),* AGN195183 (3 nM) [Kd]17–22; Am580 (36 nM), TTNPB (36–72 nM), Am80 (124 nM) [IC50]19–23; BMS75324
Antagonists BMS614 (2 nM), BMS493 (4.2 nM), AGN193109 (2–16 nM), Ro-41-5253 (60 nM) [IC50]19,22,24–28
Coactivators NCOA1, NCOA2, NCOA3, PPARBP, CREBBP, p30012,29–39
Corepressors NCOR1, NCOR240–44
Biologically important isoforms RARα1 {Hm, Mm}: transcribed from the promoter P1 and differs from RARα2 in the A domain—RARα1 is phosphorylated by cdk7/TFIIH (Ser77)5,45,46; RARα2 {Hs, Mm}: in contrast with the RARα1 isoform, RARα2 is transcribed from downstream promoter P2, which contains a DR5 and is inducible by retinoid5,47
Tissue distribution Majority of tissues {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot]6,48–54
Functional assays Inhibition of cellular proliferation of the MCF-7 breast cancer cell line expressing the estrogen receptor {Hs}55; induction of maturation of acute myeloid leukemia cell lines (NB4, PBL985, U937, HL60) using the histological nitro blue tetrazolium reaction and analysis of CD11c integrin expression by direct immunofluorescence {Hs}21,32,56 ,57; parietal endodermal differentiation in the presence of cAMP of F9 murine embryonal carcinoma cell line {Mm}58
Main target genes Activated: CYP26 {Hs, Mm, Rn},59 RARβ2 {Hs, Mm, Rn}26,57,60,61, Hoxa-1 {Mm}51,60,62 , CRBP1 {Mm}60,63, CRABPII {Mm}60,64
Mutant phenotype Abnormalities observed: growth retardation, male sterility, impaired alveolar formation; congenital defects observed: webbed digits, homeotic transformations and malformations of cervical vertebrae, pterygoquadrate cartilage, malformations of the squamosal bone; note that both the specific RARα1-null and RARα2-null mutants are apparently normal {Mm} [knockout]34,65–67
Human disease APL, a subtype of acute myelogenous leukemia: caused by several translocations that implicate the human RARα gene; the reciprocal chromosomal translocation between RARα and PML human genes produces a fusion protein PML-RARα; the use of supraphysiological doses of ATRA lead to remission in patients with APL; in contrast, the fusion protein resulting from the translocation between RARα and the PLZF is insensitive to ATRA treatment68–70

  • aa, amino acids; chr., chromosome; HRE, hormone response element; PARP-1, poly(ADP-ribose) polymerase 1; TTNPB, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-pr openyl]benzoic acid; PPARBP, peroxisome proliferator-activated receptor binding protein; CREBBP, cAMP response element-binding protein-binding protein

  • ↵* Radioligand

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  • ↵2. Petkovich M, Brand NJ, Krust A, and Chambon P (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330: 444-450

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  • ↵5. Leroy P, Krust A, Zelent A, Mendelsohn C, Garnier JM, Kastner P, Dierich A, and Chambon P (1991) Multiple isoforms of the mouse retinoic acid receptor α are generated by alternative splicing and differential induction by retinoic acid. EMBO (Eur Mol Biol Organ) J 10: 59-69

  • ↵6. Zelent A, Krust A, Petkovich M, Kastner P, and Chambon P (1989) Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin. Nature 339: 714-717

  • ↵7. Bour G, Gaillard E, Bruck N, Lalevee S, Plassat JL, Busso D, Samama JP, and Rochette-Egly C (2005) Cyclin H binding to the RARα activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7. Proc Natl Acad Sci USA 102: 16608-16613

  • ↵8. Rochette-Egly, C. (2003) Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal 15: 355-366

  • ↵9. Rochette-Egly C, Adam S, Rossignol M, Egly JM, and Chambon P (1997) Stimulation of RAR α activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Cell 90: 97-107

  • ↵10. Chen JY, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett JE, Reczek P, Chambon P, and Gronemeyer H (1995) RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO (Eur Mol Biol Org) J 14: 1187-1197

  • ↵11. Lafyatis R, Kim SJ, Angel P, Roberts AB, Sporn MB, Karin M, and Wilder RL (1990) Interleukin-1 stimulates and all-trans-retinoic acid inhibits collagenase gene expression through its 5′ activator protein-1-binding site. Mol Endocrinol 4: 973-980

  • ↵12. Nicholson RC, Mader S, Nagpal S, Leid M, Rochette-Egly C, and Chambon P (1990) Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO (Eur Mol Biol Organ) J 9: 4443-4454

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  • ↵16. Pavri R, Lewis B, Kim TK, Dilworth FJ, Erdjument-Bromage H, Tempst P, de Murcia G, Evans R, Chambon P, and Reinberg D (2005) PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol Cell 18: 83-96

  • ↵17. Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P, et al. (1993) Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 90: 30-34

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  • ↵24. Gehin M, Vivat V, Wurtz JM, Losson R, Chambon P, Moras D, and Gronemeyer H (1999) Structural basis for engineering of retinoic acid receptor isotype–selective agonists and antagonists. Chem Biol 6: 519-529

  • ↵25. Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, and Moras D (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5: 289-298

  • ↵26. Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415: 187-192

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  • ↵29. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569-580

  • ↵30. Farboud B, Hauksdottir H, Wu Y, and Privalsky ML (2003) Isotype-restricted corepressor recruitment: a constitutively closed helix 12 conformation in retinoic acid receptors β and γ interferes with corepressor recruitment and prevents transcriptional repression. Mol Cell Biol 23: 2844-2858

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  • ↵36. Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, and Gronemeyer H (1998) The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO (Eur Mol Biol Organ) J 17: 507-519

  • ↵37. Voegel JJ, Heine MJ, Zechel C, Chambon P, and Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO (Eur Mol Biol Organ) J 15: 3667-3675

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  • ↵45. Brand NJ, Petkovich M, and Chambon P (1990) Characterization of a functional promoter for the human retinoic acid receptor-α (hRAR-α). Nucleic Acids Res 18: 6799-6806

  • ↵46. van der Leede BJ, Folkers GE, Kruyt FA, and van der Saag PT (1992) Genomic organization of the human retinoic acid receptor β 2. Biochem Biophys Res Commun 188: 695-702

  • ↵47. Leroy P, Nakshatri H, and Chambon P (1991) Mouse retinoic acid receptor α 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci USA 88: 10138-10142

  • ↵48. Dolle P, Ruberte E, Kastner P, Petkovich M, Stoner CM, Gudas LJ, and Chambon P (1989) Differential expression of genes encoding α, β and γ retinoic acid receptors and CRABP in the developing limbs of the mouse. Nature 342: 702-705

  • ↵49. Dolle P, Ruberte E, Leroy P, Morriss-Kay G, and Chambon P (1990) Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110: 1133-1151

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  • ↵64. Durand B, Saunders M, Leroy P, Leid M, and Chambon P (1992) All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71: 73-85

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  • ↵67. Mark M, and Chambon P (2003) Functions of RARs and RXRs in vivo: genetic dissection of the retinoid signaling pathway. Pure Appl Chem 75: 1709-1732

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