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)* [Kd]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

  • ↵22. Onate SA, Tsai SY, Tsai MJ, and O'Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354-1357

  • ↵23. Pogenberg V, Guichou JF, Vivat-Hannah V, Kammerer S, Perez E, Germain P, de Lera AR, Gronemeyer H, Royer CA, and Bourguet W (2005) Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies. J Biol Chem 280: 1625-1633

  • ↵24. 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

  • ↵25. Yuan CX, Ito M, Fondell JD, Fu ZY, and Roeder RG (1998) The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci USA 95: 7939-7944

  • ↵26. de The H, Marchio A, Tiollais P, and Dejean A (1989) Differential expression and ligand regulation of the retinoic acid receptor α and β genes. EMBO (Eur Mol Biol Organ) J 8: 429-433

  • ↵27. 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

  • ↵28. 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

  • ↵29. Krust A, Kastner P, Petkovich M, Zelent A, and Chambon P (1989) A third human retinoic acid receptor, hRAR-γ. Proc Natl Acad Sci U S A 86: 5310-5314

  • ↵30. Ruberte E, Dolle P, Chambon P, and Morriss-Kay G (1991) Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 111: 45-60

  • ↵31. Ruberte E, Dolle P, Krust A, Zelent A, Morriss-Kay G, and Chambon P (1990) Specific spatial and temporal distribution of retinoic acid receptor γ transcripts during mouse embryogenesis. Development 108: 213-222

  • ↵32. Ghyselinck NB, Dupe V, Dierich A, Messaddeq N, Garnier JM, Rochette-Egly C, Chambon P, and Mark M (1997) Role of the retinoic acid receptor β (RARβ) during mouse development. Int J Dev Biol 41: 425-447

  • ↵33. Grondona JM, Kastner P, Gansmuller A, Decimo D, Chambon P, and Mark M (1996) Retinal dysplasia and degeneration in RARβ 2/RARγ 2 compound mutant mice. Development 122: 2173-2188

  • ↵34. Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, and Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279: 863-867

  • ↵35. 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

  • ↵36. Mark M, Ghyselinck NB, and Chambon P (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signalling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 46: 451-480

  • ↵37. Castillo L, Milano G, Santini J, Demard F, and Pierrefite V (1997) Analysis of retinoic acid receptor β expression in normal and malignant laryngeal mucosa by a sensitive and routine applicable reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay method. Clin Cancer Res 3: 2137-2142

  • ↵38. Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, Martinet Y, Martinet N, and Vignaud JM (1999) Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 91: 1059-1066

  • ↵39. Xu XC, Sozzi G, Lee JS, Lee JJ, Pastorino U, Pilotti S, Kurie JM, Hong WK, and Lotan R (1997) Suppression of retinoic acid receptor β in non-small-cell lung cancer in vivo: implications for lung cancer development, J Natl Cancer Inst 89: 624-629

  • ↵40. Qiu H, Zhang W, El-Naggar AK, Lippman SM, Lin P, Lotan R, and Xu XC (1999) Loss of retinoic acid receptor-β expression is an early event during esophageal carcinogenesis. Am J Pathol 155: 1519-1523

  • ↵41. Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E, Widschwendter A, Mayr A, Marth C, and Zeimet AG (1997) Loss of retinoic acid receptor β expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res 57: 4158-4161

  • ↵42. Widschwendter M, Berger J, Hermann M, Muller HM, Amberger A, Zeschnigk M, Widschwendter A, Abendstein B, Zeimet AG, Daxenbichler G, et al. (2000) Methylation and silencing of the retinoic acid receptor-β 2 gene in breast cancer. J Natl Cancer Inst 92: 826-832

  • ↵43. Widschwendter M, Berger J, Muller HM, Zeimet AG, and Marth C (2001) Epigenetic downregulation of the retinoic acid receptor-β 2 gene in breast cancer. J Mamm Gland Biol Neoplasia 6: 193-201

  • ↵44. Xu XC, Sneige N, Liu X, Nandagiri R, Lee JJ, Lukmanji F, Hortobagyi G, Lippman SM, Dhingra K, and Lotan R (1997) Progressive decrease in nuclear retinoic acid receptor β messenger RNA level during breast carcinogenesis. Cancer Res 57: 4992-4996

  • ↵45. Zelent A, Krust A, Petkovich M, Kastner P, and Chambon P (1989) Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature (Lond) 339: 714-717

  • ↵46. 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 beta generated by usage of two promoters and alternative splicing. EMBO (Eur Mol Biol Org) J 10: 71-81