Home LiteratureArticle Details
PMID: 15650024 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Heterodimers of retinoic acid receptors and thyroid hormone receptors display unique combinatorial regulatory properties.

Molecular endocrinology (Baltimore, Md.) ·Vol. 19 ·No. 4 ·2005-04-00 ·Pages 863-78

Lee S, Privalsky ML

Abstract

Nuclear receptors are ligand-regulated transcription factors that regulate key aspects of metazoan development, differentiation, and homeostasis. Nuclear receptors recognize target genes by binding to specific DNA recognition sequences, denoted hormone response elements (HREs). Many nuclear receptors can recognize HREs as either homodimers or heterodimers. Retinoid X receptors (RXRs), in particular, serve as important heterodimer partners for many other nuclear receptors, including thyroid hormone receptors (TRs), and RXR/TR heterodimers have been proposed to be the primary mediators of target gene regulation by T3 hormone. Here, we report that the retinoic acid receptors (RARs), a distinct class of nuclear receptors, are also efficient heterodimer partners for TRs. These RAR/TR heterodimers form with similar affinities as RXR/TR heterodimers on an assortment of consensus and natural HREs, and preferentially assemble with the RAR partner 5' of the TR moiety. The corepressor and coactivator recruitment properties of these RAR/TR heterodimers and their transcriptional activities in vivo are distinct from those observed with the corresponding RXR heterodimers. Our studies indicate that RXRs are not unique in their ability to partner with TRs, and that RARs can also serve as robust heterodimer partners and combinatorial regulators of T3-modulated gene expression.

MeSH Terms
Animals DNA-Binding Proteins/metabolism Dimerization Genes, Reporter Histone Acetyltransferases Humans Nuclear Receptor Coactivator 1 Nuclear Receptor Coactivator 3 Receptors, Retinoic Acid/metabolism Response Elements Retinoic Acid Receptor alpha Retinoid X Receptor gamma/metabolism Thyroid Hormone Receptors alpha/metabolism Transcription Factors/metabolism Transcriptional Activation Triiodothyronine/metabolism
Chemicals
DNA-Binding Proteins RARA protein, human Receptors, Retinoic Acid Retinoic Acid Receptor alpha Retinoid X Receptor gamma Thyroid Hormone Receptors alpha Transcription Factors Triiodothyronine Histone Acetyltransferases NCOA1 protein, human Nuclear Receptor Coactivator 1 Nuclear Receptor Coactivator 3
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Lee Sangho
Section of Microbiology, One Shields Avenue, University of California at Davis, Davis, California 95616, USA.
Privalsky Martin L
References (82)
82 references, click to expand
  1. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene.
    Nature. 1990 Jan 11;343(6254):177-80 PMID: 2153268
  2. The viral erbA oncogene protein, a constitutive repressor in animal cells, is a hormone-regulated activator in yeast.
    Cell. 1990 Dec 21;63(6):1277-86 PMID: 1979758
  3. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase.
    Anal Biochem. 1991 Feb 1;192(2):262-7 PMID: 1852137
  4. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
    Cell. 1991 Jun 28;65(7):1255-66 PMID: 1648450
  5. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors.
    Cell. 1991 Jun 28;65(7):1267-79 PMID: 1648451
  6. Differential DNA binding by monomeric, homodimeric, and potentially heteromeric forms of the thyroid hormone receptor.
    Mol Cell Biol. 1991 Oct;11(10):5005-15 PMID: 1922030
  7. Thyroid hormone: half-sites and insights. Molecular Approaches to the Study of Thyroid hormone Action: a Keystone Symposium, Tamarron, CO, USA, March 8-14, 1991.
    New Biol. 1991 Sep;3(9):835-44 PMID: 1931826
  8. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently.
    Cell. 1992 Jan 24;68(2):377-95 PMID: 1310259
  9. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors.
    Nature. 1992 Jan 30;355(6359):441-6 PMID: 1310350
  10. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
    Nature. 1992 Jan 30;355(6359):446-9 PMID: 1310351
  11. Triiodothyronine (T3) decreases binding to DNA by T3-receptor homodimers but not receptor-auxiliary protein heterodimers.
    J Biol Chem. 1992 Feb 25;267(6):3565-8 PMID: 1740410
  12. A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor.
    EMBO J. 1992 Mar;11(3):1015-23 PMID: 1347744
  13. Half-site spacing and orientation determines whether thyroid hormone and retinoic acid receptors and related factors bind to DNA response elements as monomers, homodimers, or heterodimers.
    Mol Endocrinol. 1992 Mar;6(3):429-42 PMID: 1316541
  14. Capacity for cooperative binding of thyroid hormone (T3) receptor dimers defines wild type T3 response elements.
    Mol Endocrinol. 1992 Apr;6(4):502-14 PMID: 1584220
  15. Heterodimerization of thyroid hormone (TH) receptor with H-2RIIBP (RXR beta) enhances DNA binding and TH-dependent transcriptional activation.
    Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5572-6 PMID: 1608968
  16. Triiodothyronine (T3) differentially affects T3-receptor/retinoic acid receptor and T3-receptor/retinoid X receptor heterodimer binding to DNA.
    J Biol Chem. 1992 Nov 15;267(32):23248-52 PMID: 1331079
  17. Characterization of the thyroid hormone response element in the skeletal alpha-actin gene: negative regulation of T3 receptor binding by the retinoid X receptor.
    Cell Growth Differ. 1993 Apr;4(4):269-79 PMID: 8388243
  18. Thyroid hormone receptors: multiple forms, multiple possibilities.
    Endocr Rev. 1993 Apr;14(2):184-93 PMID: 8325251
  19. Thyroid hormone receptor coactivators and corepressors.
    Thyroid. 1998 Aug;8(8):703-13 PMID: 9737367
  20. Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor.
    J Cell Biochem. 1999 Dec 1;75(3):462-80 PMID: 10536369
  21. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways.
    Recent Prog Horm Res. 1999;54:345-67; discussion 367-8 PMID: 10548883
  22. Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function.
    J Cell Biochem. 1999;Suppl 32-33:110-22 PMID: 10629110
  23. The coregulator exchange in transcriptional functions of nuclear receptors.
    Genes Dev. 2000 Jan 15;14(2):121-41 PMID: 10652267
  24. Resistance to thyroid hormone (RTH) syndrome reveals novel determinants regulating interaction of T3 receptor with corepressor.
    Mol Cell Endocrinol. 2000 Jan 25;159(1-2):109-24 PMID: 10687857
  25. The mechanism of action of thyroid hormones.
    Annu Rev Physiol. 2000;62:439-66 PMID: 10845098
  26. The nuclear corepressors recognize distinct nuclear receptor complexes.
    Mol Endocrinol. 2000 Jun;14(6):900-14 PMID: 10847591
  27. Steroid hormone receptors: an update.
    Hum Reprod Update. 2000 May-Jun;6(3):225-36 PMID: 10874567
  28. Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains.
    Mol Cell. 2000 Feb;5(2):289-98 PMID: 10882070
  29. The SMRT corepressor is regulated by a MEK-1 kinase pathway: inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export.
    Mol Cell Biol. 2000 Sep;20(17):6612-25 PMID: 10938135
  30. COUP-TF orphan nuclear receptors in development and differentiation.
    Cell Mol Life Sci. 2000 Sep;57(10):1388-98 PMID: 11078018
  31. The nuclear receptor corepressor (N-CoR) contains three isoleucine motifs (I/LXXII) that serve as receptor interaction domains (IDs).
    Mol Endocrinol. 2000 Dec;14(12):1976-85 PMID: 11117528
  32. Corepressors and nuclear hormone receptor function.
    Curr Top Microbiol Immunol. 2001;254:101-16 PMID: 11190569
  33. Regulation of SMRT and N-CoR corepressor function.
    Curr Top Microbiol Immunol. 2001;254:117-36 PMID: 11190570
  34. Retinoid X receptor and its partners in the nuclear receptor family.
    Curr Opin Struct Biol. 2001 Feb;11(1):33-8 PMID: 11179889
  35. DNA recognition by the aberrant retinoic acid receptors implicated in human acute promyelocytic leukemia.
    Cell Growth Differ. 2001 Feb;12(2):85-98 PMID: 11243468
  36. Determinants for selective RAR and TR recognition of direct repeat HREs.
    Genes Dev. 1993 Jul;7(7B):1411-22 PMID: 8392478
  37. Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers.
    Genes Dev. 1993 Jul;7(7B):1423-35 PMID: 8392479
  38. Reconstitution of retinoid X receptor function and combinatorial regulation of other nuclear hormone receptors in the yeast Saccharomyces cerevisiae.
    Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6929-33 PMID: 8394003
  39. Nonbiased identification of DNA sequences that bind thyroid hormone receptor alpha 1 with high affinity.
    J Biol Chem. 1993 Sep 15;268(26):19392-7 PMID: 8366086
  40. The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.
    Mol Cell Biol. 1993 Oct;13(10):5970-80 PMID: 8105369
  41. Activation of myoD gene transcription by 3,5,3'-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors.
    Nucleic Acids Res. 1994 Feb 25;22(4):583-91 PMID: 8127707
  42. A novel heterodimerization partner for thyroid hormone receptor. Peroxisome proliferator-activated receptor.
    J Biol Chem. 1994 Apr 22;269(16):11683-6 PMID: 8163464
  43. Vitamin D3-thyroid hormone receptor heterodimer polarity directs ligand sensitivity of transactivation.
    Nature. 1994 Aug 4;370(6488):382-6 PMID: 8047145
  44. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding.
    Nature. 1994 Oct 6;371(6497):528-31 PMID: 7935766
  45. Nuclear hormone receptors activate direct, inverted, and everted repeats.
    Ann N Y Acad Sci. 1995 Jun 12;761:29-37 PMID: 7625727
  46. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.
    Nature. 1995 Oct 5;377(6548):397-404 PMID: 7566114
  47. Polarity-specific activities of retinoic acid receptors determined by a co-repressor.
    Nature. 1995 Oct 5;377(6548):451-4 PMID: 7566126
  48. A transcriptional co-repressor that interacts with nuclear hormone receptors.
    Nature. 1995 Oct 5;377(6548):454-7 PMID: 7566127
  49. The nuclear receptor superfamily: the second decade.
    Cell. 1995 Dec 15;83(6):835-9 PMID: 8521507
  50. The RXR heterodimers and orphan receptors.
    Cell. 1995 Dec 15;83(6):841-50 PMID: 8521508
  51. DNA recognition by normal and oncogenic thyroid hormone receptors. Unexpected diversity in half-site specificity controlled by non-zinc-finger determinants.
    J Biol Chem. 1996 May 3;271(18):10800-5 PMID: 8631892
  52. A decade of molecular biology of retinoic acid receptors.
    FASEB J. 1996 Jul;10(9):940-54 PMID: 8801176
  53. Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors.
    Mol Endocrinol. 1996 Jul;10(7):813-25 PMID: 8813722
  54. Some new twists in the regulation of gene expression by thyroid hormone and retinoic acid receptors.
    J Endocrinol. 1996 Sep;150(3):349-57 PMID: 8882153
  55. The phantom ligand effect: allosteric control of transcription by the retinoid X receptor.
    Genes Dev. 1997 Feb 1;11(3):299-308 PMID: 9030683
  56. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors.
    Mol Endocrinol. 1997 Apr;11(4):470-80 PMID: 9092799
  57. Stoichiometric and steric principles governing repression by nuclear hormone receptors.
    Genes Dev. 1997 Apr 1;11(7):835-46 PMID: 9106656
  58. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.
    J Mol Endocrinol. 1997 Dec;19(3):207-26 PMID: 9460643
  59. Coactivation and corepression in transcriptional regulation by steroid/nuclear hormone receptors.
    Crit Rev Eukaryot Gene Expr. 1998;8(2):169-90 PMID: 9714896
  60. Signaling by tyrosine kinases negatively regulates the interaction between transcription factors and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor.
    Mol Endocrinol. 1998 Aug;12(8):1161-71 PMID: 9717842
  61. Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation.
    Mol Endocrinol. 1998 Sep;12(9):1367-79 PMID: 9731705
  62. Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies.
    Recent Prog Horm Res. 1998;53:351-92; discussion 392-4 PMID: 9769715
  63. Two separate NCoR (nuclear receptor corepressor) interaction domains mediate corepressor action on thyroid hormone response elements.
    Mol Endocrinol. 1998 Oct;12(10):1567-81 PMID: 9773980
  64. Coactivators and corepressors as mediators of nuclear receptor function: an update.
    Mol Cell Endocrinol. 1998 Aug 25;143(1-2):1-7 PMID: 9806345
  65. Molecular and structural biology of thyroid hormone receptors.
    Clin Exp Pharmacol Physiol Suppl. 1998 Nov;25:S2-11 PMID: 9809185
  66. Coactivator and corepressor complexes in nuclear receptor function.
    Curr Opin Genet Dev. 1999 Apr;9(2):140-7 PMID: 10322133
  67. Transcription factors: the right combination for the DNA lock.
    Curr Biol. 1999 Jun 17;9(12):R456-8 PMID: 10375516
  68. The structure of the nuclear hormone receptors.
    Steroids. 1999 May;64(5):310-9 PMID: 10406480
  69. Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions.
    J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):3-12 PMID: 10418975
  70. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.
    Arch Biochem Biophys. 1999 Sep 1;369(1):11-23 PMID: 10462436
  71. Transcriptional coregulators of the nuclear receptor superfamily: coactivators and corepressors.
    Cell Mol Life Sci. 2001 Feb;58(2):289-97 PMID: 11289310
  72. The TRAP/SMCC/Mediator complex and thyroid hormone receptor function.
    Trends Endocrinol Metab. 2001 Apr;12(3):127-34 PMID: 11306338
  73. Mediator complexes and transcription.
    Curr Opin Cell Biol. 2001 Jun;13(3):274-80 PMID: 11343897
  74. Transcriptional repression by thyroid hormone receptors. A role for receptor homodimers in the recruitment of SMRT corepressor.
    J Biol Chem. 2001 May 18;276(20):16857-67 PMID: 11278601
  75. Nuclear-receptor interactions on DNA-response elements.
    Trends Biochem Sci. 2001 Jun;26(6):384-90 PMID: 11406412
  76. Co-regulator recruitment and the mechanism of retinoic acid receptor synergy.
    Nature. 2002 Jan 10;415(6868):187-92 PMID: 11805839
  77. Minireview: nuclear receptor coactivators--an update.
    Endocrinology. 2002 Jul;143(7):2461-5 PMID: 12072374
  78. PPARs: transcriptional effectors of fatty acids and their derivatives.
    Cell Mol Life Sci. 2002 May;59(5):790-8 PMID: 12088279
  79. The atypical interaction of peroxisome proliferator-activated receptor alpha with liver X receptor alpha antagonizes the stimulatory effect of their respective ligands on the murine cholesterol 7alpha-hydroxylase gene promoter.
    Biochim Biophys Acta. 2002 Jul 11;1583(2):229-36 PMID: 12117567
  80. Retinoic acid receptors beta and gamma do not repress, but instead activate target gene transcription in both the absence and presence of hormone ligand.
    Mol Endocrinol. 2003 Mar;17(3):373-85 PMID: 12554770
  81. The role of corepressors in transcriptional regulation by nuclear hormone receptors.
    Annu Rev Physiol. 2004;66:315-60 PMID: 14977406
  82. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer.
    Cell. 1989 Nov 17;59(4):697-708 PMID: 2555064
Article Info
Journal
Molecular endocrinology (Baltimore, Md.)
Abbr.
Mol Endocrinol
ISSN
0888-8809
DOI
10.1210/me.2004-0210
Published
2005-04-00
Epub
2005-00-13
Pages
863-78
Language
English
Region
United States
NLM ID
8801431
PMCID
PMC2675561
Subset
IM
Grants
NCI NIH HHS · R37 CA053394 · United States
NIDDK NIH HHS · R01 DK053528-07 · United States
NIDDK NIH HHS · R01 DK053528 · United States
NCI NIH HHS · R37 CA53394 · United States
NIDDK NIH HHS · R01 DK053528-10 · United States
External Links
PubMed source DOI: 10.1210/me.2004-0210 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2