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)* [Kd]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

  • ↵1. Ishikawa T, Umesono K, Mangelsdorf DJ, Aburatani H, Stanger BZ, Shibasaki Y, Imawari M, Evans RM, and Takaku F (1990) A functional retinoic acid receptor encoded by the gene on human chromosome 12. Mol Endocrinol 4: 837-844

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

  • ↵3. 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

  • ↵4. Laudet V and Gronemeyer H (2002) The Nuclear Receptor Facts Book, Academic Press, San Diego

  • ↵5. Lopes da Silva S, Van Horssen AM, Chang C, and Burbach JP (1995) Expression of nuclear hormone receptors in the rat supraoptic nucleus. Endocrinology 136: 2276-2283

  • ↵6. Kastner P, Krust A, Mendelsohn C, Garnier JM, Zelent A, Leroy P, Staub A, and Chambon P (1990) Murine isoforms of retinoic acid receptor γ with specific patterns of expression. Proc Natl Acad Sci USA 87: 2700-2704

  • ↵7. 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

  • ↵8. 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

  • ↵9. 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

  • ↵10. Schule R, Rangarajan P, Yang N, Kliewer S, Ransone LJ, Bolado J, Verma IM, and Evans RM (1991) Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci USA 88: 6092-6096

  • ↵11. Schule R, Umesono K, Mangelsdorf DJ, Bolado J, Pike JW, and Evans RM (1990) Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell 61: 497-504

  • ↵12. Bastien J, Adam-Stitah S, Riedl T, Egly JM, Chambon P, and Rochette-Egly C (2000) TFIIH interacts with the retinoic acid receptor γ and phosphorylates its AF-1-activating domain through cdk7. J Biol Chem 275: 21896-21904

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

  • ↵14. Gianni M, Bauer A, Garattini E, Chambon P, and Rochette-Egly C (2002) Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RAR γ degradation and transactivation. EMBO (Eur Mol Biol Organ) J 21: 3760-3769

  • ↵15. Gianni M, Kopf E, Bastien J, Oulad-Abdelghani M, Garattini E, Chambon P, and Rochette-Egly C (2002) Down-regulation of the phosphatidylinositol 3-kinase/Akt pathway is involved in retinoic acid-induced phosphorylation, degradation, and transcriptional activity of retinoic acid receptor γ 2. J Biol Chem 277: 24859-24862

  • ↵16. Bour G, Plassat JL, Bauer A, Lalevee S, and Rochette-Egly C (2005) Vinexin β interacts with the non-phosphorylated AF-1 domain of retinoid receptor γ (RARγ) and represses RARγ -mediated transcription. J Biol Chem 280: 17027-17037

  • ↵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

  • ↵18. 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

  • ↵19. 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

  • ↵20. 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

  • ↵21. Thacher SM, Vasudevan J, and Chandraratna RA (2000) Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des 6: 25-58

  • ↵22. Bernard BA, Bernardon JM, Delescluse C, Martin B, Lenoir MC, Maignan J, Charpentier B, Pilgrim WR, Reichert U, and Shroot B (1992) Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor γ. Biochem Biophys Res Commun 186: 977-983

  • ↵23. Klaholz BP, Mitschler A, Belema M, Zusi C, and Moras D (2000) Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARγ. Proc Natl Acad Sci USA 97: 6322-6327

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

  • ↵25. 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

  • ↵26. 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

  • ↵27. Szondy Z, Reichert U, Bernardon JM, Michel S, Toth R, Ancian P, Ajzner E, and Fesus L (1997) Induction of apoptosis by retinoids and retinoic acid receptor γ-selective compounds in mouse thymocytes through a novel apoptosis pathway. Mol Pharmacol 51: 972-982

  • ↵28. 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

  • ↵29. 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

  • ↵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

  • ↵31. McKenna NJ, Lanz RB, and O'Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321-344

  • ↵32. 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

  • ↵33. 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

  • ↵34. 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

  • ↵35. Chen JD and Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377: 454-457

  • ↵36. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, et al. (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377: 397-404

  • ↵37. Sande S and Privalsky ML (1996) Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors. Mol Endocrinol 10: 813-825

  • ↵38. Wong CW and Privalsky ML (1998) Transcriptional silencing is defined by isoform- and heterodimer-specific interactions between nuclear hormone receptors and corepressors. Mol Cell Biol 18: 5724-5733

  • ↵39. Lehmann JM, Hoffmann B, and Pfahl M (1991) Genomic organization of the retinoic acid receptor γ gene. Nucleic Acids Res 19: 573-578

  • ↵40. Bastien J, Plassat JL, Payrastre B, and Rochette-Egly C (2006) The phosphoinositide 3-kinase/Akt pathway is essential for the retinoic acid-induced differentiation of F9 cells. Oncogene 25: 2040-2047

  • ↵41. Giguere V, Shago M, Zirngibl R, Tate P, Rossant J, and Varmuza S (1990) Identification of a novel isoform of the retinoic acid receptor γ expressed in the mouse embryo. Mol Cell Biol 10: 2335-2340

  • ↵42. Lehmann JM, Zhang XK, and Pfahl M (1992) RAR γ 2 expression is regulated through a retinoic acid response element embedded in Sp1 sites. Mol Cell Biol 12: 2976-2985

  • ↵43. Taneja R, Rochette-Egly C, Plassat JL, Penna L, Gaub MP, and Chambon P (1997) Phosphorylation of activation functions AF-1 and AF-2 of RARα and RARγ is indispensable for differentiation of F9 cells upon retinoic acid and cAMP treatment. EMBO (Eur Mol Biol Organ) J 16: 6452-6465

  • ↵44. 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

  • ↵45. 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

  • ↵46. Haq R, Pfahl M, and Chytil F (1991) Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats. Proc Natl Acad Sci USA 88: 8272-8276

  • ↵47. 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

  • ↵48. Chiba H, Clifford J, Metzger D, and Chambon P (1997) Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells. Mol Cell Biol 17: 3013-3020

  • ↵49. Rochette-Egly C and Chambon P (2001) F9 embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling. Histol Histopathol 16: 909-922

  • ↵50. Vasios GW, Gold JD, Petkovich M, Chambon P, and Gudas LJ (1989) A retinoic acid-responsive element is present in the 5′ flanking region of the laminin B1 gene. Proc Natl Acad Sci USA 86: 9099-9103

  • ↵51. de The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, and Dejean A (1990) Identification of a retinoic acid responsive element in the retinoic acid receptor β gene. Nature 343: 177-180

  • ↵52. Ferrari N, Pfahl M, and Levi G (1998) Retinoic acid receptor γ 1 (RARγ 1) levels control RARβ 2 expression in SK-N-BE2(c) neuroblastoma cells and regulate a differentiation-apoptosis switch. Mol Cell Biol 18: 6482-6492

  • ↵53. Dupe V, Davenne M, Brocard J, Dolle P, Mark M, Dierich A, Chambon P, and Rijli FM (1997) In vivo functional analysis of the Hoxa-1 3′ retinoic acid response element (3′RARE). Development 124: 399-410

  • ↵54. Smith WC, Nakshatri H, Leroy P, Rees J, and Chambon P (1991) A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO (Eur Mol Biol Organ) J 10: 2223-2230

  • ↵55. 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

  • ↵56. Chapellier B, Mark M, Messaddeq N, Calleja C, Warot X, Brocard J, Gerard C, Li M, Metzger D, Ghyselinck NB, et al. (2002) Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled. EMBO (Eur Mol Biol Organ) J 21: 3402-3413

  • ↵57. 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

  • ↵58. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, and Chambon P (1993) Function of retinoic acid receptor γ in the mouse. Cell 73: 643-658

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

  • ↵60. 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

  • ↵61. Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, and Voorhees JJ (1996) Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379: 335-339

  • ↵62. Fisher GJ, and Voorhees JJ (1996) Molecular mechanisms of retinoid actions in skin. FASEB J 10: 1002-1013

  • ↵63. Wang Z, Boudjelal M, Kang S, Voorhees JJ, and Fisher GJ (1999) Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med 5: 418-422