International Union of Pharmacology. LX. Retinoic Acid Receptors

Pierre Germain; Pierre Chambon; Gregor Eichele; Ronald M. Evans; Mitchell A. Lazar; Mark Leid; Angel R. De Lera; Reuben Lotan; David J. Mangelsdorf; Hinrich Gronemeyer

doi:10.1124/pr.58.4.4

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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) [K_d]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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↵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
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↵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
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TABLE 2

RARβ

Receptor Nomenclature	NR1B2
Receptor code	4.10.1:RA:1:B2
Other names	Hap
Molecular information	Hs: 455aa, P10826, chr. 3p24¹^,²⁶
	Rn: chr. 15²⁶
	Mm: 482aa, P22605, chr. 14 A²⁶^,²⁸^,⁴⁵^,⁴⁶
DNA binding
Structure	Heterodimer, RXR partner
HRE core sequence	PuG(G/T)TCA (DR5)
Partners	AP-1 (functional): RARβ inhibits AP-1-driven transactivation⁴^,³⁰
Agonists	9-cis-Retinoic acid (0.2 nM),^* all-trans-retinoic acid (0.4 nM)^* [K_d]¹⁴^,¹⁵^,²⁹^,³⁷; BMS641 (2.5 nM), TTNPB (5–22 nM) [IC₅₀]¹⁰^,¹⁴^,¹⁵^,²⁹^,³⁷
Antagonists	BMS493 (2.9 nM), AGN193109 (2–7 nM) [IC₅₀]⁹^,¹⁶^,¹⁷^,³⁷
Coactivators	NCOA1, NCOA2, NCOA3, PPARBP³^,⁸^,⁹^,²⁰^–²³^,²⁷^,³¹^,³³^,³⁸^,⁴⁴
Biologically important isoforms	RARβ 1 {Hs, Mm}: differs from RARβ 2 in the A domain⁴⁶; RARβ 2 {Hs, Mm}: in contrast to the RARβ 1 isoform, RARβ 2 is transcribed from promoter (the downstream one, P2) that contains a DR5 and is inducible by retinoid⁴⁶; RARβ 3 {Mm}: the RARβ 3 isoform is generated from the promoter P1 and differs from RARβ 1 by its N-terminal part—not detected in human⁴⁶; RARβ 4 {Hs, Mm}: RARβ 4 is generated from the promoter P2 and differs from RARβ 2 by its N terminus that initiates a non-AUG codon, CUG²⁸
Tissue distribution	Brain, liver, kidney, heart, pituitary, colon, uterus, ovary, testis, prostate, adrenal, eye {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot]⁵^–⁷^,¹³^,¹⁹^,³⁵^,³⁶
Mutant phenotype	Abnormalities observed: growth retardation, behavioral defects, altered alveolar formation; congenital defects observed: homeotic transformations and malformations of cervical vertebrae, persistence and hyperplasia of the primary vitreous body; note that specific RARβ 1/β 3-null mutants are apparently normal, and specific RARβ 2/β 4-null mutants exhibited persistence and hyperplasia of the primary vitreous body {Mm} [knockout]¹¹^,¹²^,¹⁸^,²⁴^,²⁵
Human disease	Human nonsmall cell lung cancer: associated with loss of RARβ expression²^,³²^,⁴³; human esophageal cancer: associated with loss of RARβ expression³⁴; human breast cancer: associated with loss of RARβ expression³⁹^–⁴²

aa, amino acids; chr., chromosome; HRE, hormone response element; 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
↵* Radioligand
↵1. Brand N, Petkovich M, Krust A, Chambon P, de The H, Marchio A, Tiollais P, and Dejean A (1988) Identification of a second human retinoic acid receptor. Nature 332: 850-853
↵2. Mattei MG, Riviere M, Krust A, Ingvarsson S, Vennstrom B, Islam MQ, Levan G, Kautner P, Zelent A, Chambon P, et al. (1991) Chromosomal assignment of retinoic acid receptor (RAR) genes in the human, mouse, and rat genomes. Genomics 10: 1061-1069
↵3. Nagpal S, Zelent A, and Chambon P (1992) RAR-β 4, a retinoic acid receptor isoform, is generated from RAR-β 2 by alternative splicing and usage of a CUG initiator codon. Proc Natl Acad Sci USA 89: 2718-2722
↵4. 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
↵5. Zelent A, Mendelsohn C, Kastner P, Krust A, Garnier JM, Ruffenach F, Leroy P, and Chambon P (1991) Differentially expressed isoforms of the mouse retinoic acid receptor β generated by usage of two promoters and alternative splicing. EMBO (Eur Mol Biol Organ) J 10: 71-81
↵6. 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 Organ) J 14: 1187-1197
↵7. 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
↵8. Keidel S, LeMotte P, and Apfel C (1994) Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping. Mol Cell Biol 14: 287-298
↵9. Klaholz BP, Mitschler A, and Moras D (2000) Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. J Mol Biol 302: 155-170
↵10. Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA, and Davies PJ (1995) Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 15: 3540-3551
↵11. Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58
↵12. Germain P, Kammerer S, Perez E, Peluso-Iltis C, Tortolani D, Zusi FC, Starrett J, Lapointe P, Daris JP, Marinier A, et al. (2004) Rational design of RAR-selective ligands revealed by RARβ crystal structure. EMBO (Eur Mol Biol Organ) Rep 5: 877-882
↵13. Germain P, Iyer J, Zechel C, and Gronemeyer H (2002) Coregulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415: 187-192
↵14. Klein ES, Pino ME, Johnson AT, Davies PJ, Nagpal S, Thacher SM, Krasinski G, and Chandraratna RA (1996) Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists. J Biol Chem 271: 22692-22696
↵15. Klein ES, Wang JW, Khalifa B, Gavigan SA, and Chandraratna RA (2000) Recruitment of nuclear receptor corepressor and coactivator to the retinoic acid receptor by retinoid ligands: influence of DNA-heterodimer interactions. J Biol Chem 275: 19401-19408
↵16. 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
↵17. 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
↵18. Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book, Academic Press, San Diego
↵19. Lemon BD and Freedman LP (1999) Nuclear receptor cofactors as chromatin remodelers. Curr Opin Genet Dev 9: 499-504
↵20. Li H, Gomes PJ, and Chen JD (1997) RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci USA 94: 8479-8484
↵21. McKenna NJ, Lanz RB, and O'Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321-344
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TABLE 3

RARγ

Receptor Nomenclature	NR1B3
Receptor code	4.10.1:RA:1:B3
Molecular information	Hs: 454aa, P13631, chr. 12q13¹^–³
	Rn: chr. 7³^–⁵
	Mm: 458aa, P18911, chr. 15 F³^,⁶
DNA binding
Structure	Heterodimer, RXR partner
HRE core sequence	PuG(G/T)TCA (DR2, DR5)
Partners	AP-1 (functional): RARγ inhibits AP-1-driven transactivation⁷^–¹¹; cdk7/TFIIH (physical, functional): TFIIH phosphorylates RARγ 2 in its A/B region (Ser⁶⁸) by cdk7 subunit¹²^,¹³; p38 MAPK (functional): required for RA-induced RARγ degradation and transactivation¹³^–¹⁵; SUG1 (physical, functional): required for RA-induced RARγ degradation and transactivation¹³^–¹⁵; vinexin β (physical, functional): interacts with AF-1 domain of RARγ and represses RAR-mediated transcription¹⁶
Agonists	All-trans-retinoic acid (0.2 nM),^* 9-cis-retinoic acid (0.8 nM)^* [K_d]¹⁷^–²¹ ; TTNPB (15–26 nM), CD666 (68 nM), BMS270394 (528 nM), BMS961 (500 nM) [IC₅₀]¹⁸^–²³
Antagonists	AGN193109 (3–7 nM), BMS493 (98 nM), CD2665 (81 nM) [IC₅₀]²¹^,²⁴^–²⁷
Coactivators	NCOA1, NCOA2, NCOA3⁴^,²⁸^–³⁴
Corepressors	NCOR1, NCOR2²⁹^,³¹^,³⁵^–³⁸
Biologically important isoforms	RARγ 1 {Hs, Mm}: differs from RARγ 2 in its N-terminal domain⁶^,³⁹; RARγ 2 {Hs, Mm}: the expression of RARγ 2 is regulated through a specific RARE element; RARγ 2 is phosphorylated by p38 MAPK (Ser⁶⁶) and by cdk7/TFIIH (Ser⁶⁸) {Hs, Mm}⁶^,¹²^,¹⁴^,¹⁵^,⁴⁰^–⁴³
Tissue distribution	Highly expressed in the epidermis {Hs, Mm} [Northern blot, in situ hybridization, Western blot]²^,⁶^,⁴¹^,⁴⁴^–⁴⁷
Functional assays	Primitive endodermal differentiation and morphological differentiation of the F9 murine embryonal carcinoma cell line {Mm}⁴⁸^–⁵⁰
Main target genes	Activated: laminin B1 {Mm}⁵⁰, RARβ 2 {Hs, Mm, Rn}⁴⁸^,⁵¹^,⁵², Hoxa-1 {Mm}⁴^,⁴⁸^,⁵³, CRBP1 {Mm}⁴⁸^,⁵⁴, CRABPII {Mm}⁴⁸^,⁵⁵; repressed:
Mutant phenotype	Abnormalities observed: growth deficiency, male sterility, squamous epithelia of various epithelia, impaired alveolar formation; congenital defects observed: webbed digits, homeotic transformations and malformations of cervical vertebrae, malformed laryngeal cartilages and tracheal rings, agenesis of the Harderian glands, agenesis of the metopic pillar of the skull, abnormal differentiation of granular keratinocytes; note that specific RARγ 2-null mutants are apparently normal, and specific RARγ 1-null mutants exhibited a growth deficiency, malformations of cervical vertebrae, and abnormal differentiation of granular keratinocytes {Mm} [knockout]⁵⁶^–⁶⁰
Human disease	Photoaging: level of RARγ is reduced after UV treatment of human skin⁶¹^–⁶³

aa, amino acids; chr., chromosome; HRE, hormone response element; TFIIH, transcription factor IIH; TTNPB, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-pr openyl]benzoic acid
↵* Radioligand
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