Dominant Negative Activity by Estrogen and Progesterone Receptors

  • Paul M. Yen
Part of the Hormones in Health and Disease book series (HHD)


Studies on the autosomal dominant syndrome of thyroid hormone resistance have shown that affected patients have a mutant allele for one of the thyroid hormone receptor (TR) isoforms, TRβ (Refetoff et al, 1993). These mutations usually alter codons in the carboxy-terminal domain and often result in decreased ligand-binding affinity. Additionally, the natural mutant receptors are able to block the transcriptional activation by both wild-type receptor isoforms (TRα and TRβ), and thus have “dominant negative activity” on this TR function. The mechanism for the dominant negative activity by mutant TRβ appears to be competition for DNA binding to TREs between mutant TR complexes (homo — and/or heterodimers) and ligandbound wild-type TR (Figure 1, panel B) (Nagaya et al, 1992; Yen et al, 1992). The exclusion of transcriptionally active TR complexes from binding to the TRE results in blockade of T3-stimulated transcriptional activation.


Progesterone Receptor Thyroid Hormone Receptor Nuclear Hormone Receptor Hormone Response Element Nuclear Hormone Receptor Superfamily 
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  1. Bamberger CM, Bamberger A-M, DeCastro M, and Chrousos GP (1995): The glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95: 2435–2441.PubMedCrossRefGoogle Scholar
  2. Baniahmad A, Ha I, Reinberg D, Tsai MJ, Tsai SY, and O’Malley BW (1993): Interaction of human thyroid hormone receptor β with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. Proc Natl Acad Sci USA 90: 8832–8836.PubMedCrossRefGoogle Scholar
  3. Barettino D, Ruiz MM, Vivanco, and Stunnenberg HG (1994): Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J 13: 3039–3049.PubMedGoogle Scholar
  4. Cadepond F, Jibard N, Schweizer-Groyer G, Segard-Manuel I, and Baulieu E (1995): Transcriptional properties of mutated glucocortico-steroid receptor (GR) derivatives coexpressed with wild-type GR. Endocrine Society Meeting, Washington, DC.Google Scholar
  5. Cavailles V, Dauvois S, L’ Horset F, Lopez G, Hoare S, Kushner PJ, and Parker MG (1995): Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 14: 3741–3751.PubMedGoogle Scholar
  6. Chen DJ and Evans RM (1995): A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377: 454–457PubMedCrossRefGoogle Scholar
  7. Conneely OM, Lydon JP, DeMayo FJ, Shymala G, and O’Malley BW (1995): Physiological consequences of progesterone receptor ablation in mice. Endocrine Society Meeting, Washington, DC.Google Scholar
  8. Fuqua SA, Fitzgerald SD, Alfred DC, Elledge RM, Nawaz Z, Mc Donnell DP, O’Malley BW, and Mc Guire WL (1992): Inhibition of estrogen receptor action by a naturally occurring variant in human breast cancer. Cancer Res 52: 483–486PubMedGoogle Scholar
  9. Giguere V, Hollenberg SM, Rosenfeld MG, and Evans RM (1986): Functional domains of the human glucocorticoid receptor. Cell 46: 645–652.PubMedCrossRefGoogle Scholar
  10. Glass CK (1994): Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers. Endocrine Rev 15: 391–407.Google Scholar
  11. Glass CK, Lipkin SM, Devary OV, and Rosenfeld MG (1989): Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer. Cell 59: 697–708.PubMedCrossRefGoogle Scholar
  12. Graupner G, Zhang XK, Tzukerman M, Wills K, Hermann T, and Pfahl M (1991): Thyroid hormone receptors repress estrogen receptor activation of a TRE. Mol Endocrinol 5: 365–372.PubMedCrossRefGoogle Scholar
  13. Halachmi S, Marden E, Martin G, Mac Kay H, Abbondanze C, and Brown M (1994): Estrogen receptor-associated proteins: Possible mediators of hormone-induced transcription. Science 264: 1455–1458.PubMedCrossRefGoogle Scholar
  14. Hollenberg SM and Evans RM (1988): Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell 55: 899–906.PubMedCrossRefGoogle Scholar
  15. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, and Rosenfeld MG (1995): Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear co-repressor. Nature 377: 397–404.PubMedCrossRefGoogle Scholar
  16. Imakado S, Bickenbach JR, Bundman DS, Rothnagel JA, Attar PS, Wang X-J, Wal czakk VR, Wisniewski S, Pote J, Gordon JS, Heyman RA, Evans RM and Roop DS (1995): Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes and Development 9: 317–329.PubMedCrossRefGoogle Scholar
  17. Ince BA, Zhuang Y, Wrenn CK, Shapiro DJ, and Katzenellenbogen BS (1993): Powerful dominant negative mutants of the human estrogen receptor. J Biol Chem 268: 14026–14032.PubMedGoogle Scholar
  18. Jacq X, Brou C, Lutz Y, Davidson I, Chambon P, and Tora L (1994): Human TAF130 is present in a distinict TFIID complex and is required for transcripitonal activation by the estrogen receptor. Cell 79: 107–117.PubMedCrossRefGoogle Scholar
  19. Kraus WL, Weis KE, and Katzenellenbogen BS (1995): Inhibitory cross-talk between steroid hormone receptors: Differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist — and antagonist-occupied progestin receptors. Mol Cell Biol 15: 1847–1857.PubMedGoogle Scholar
  20. Kurokawa R, Soderstrom M, Horlein, Halachmi S, Brown M, Rosenfeld MG, and Glass CK (1995): Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377: 451–454.PubMedCrossRefGoogle Scholar
  21. Lanz RB and Rusconi S (1994): A conserved carboxy-terminal subdomain is important for ligand interpretation and transactivation by nuclear receptors. Endocrinology 135: 2183–2195.PubMedCrossRefGoogle Scholar
  22. Lazar MA (1993): Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocrine Rev 14: 348–399.Google Scholar
  23. LeDouarin B, Zechel C, Gamier JM, Lutz Y, Tora L, Pierrat P, Heery D, Gronemeyer H, Chambon P, and Losson R (1995): The n-terminal part of TIF-1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J 14: 2020–2033.Google Scholar
  24. Lee JW, Choi HS, Gyuris J, Brent R, and Moore DD (1995a): Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol 9: 243–254.PubMedCrossRefGoogle Scholar
  25. Lee JW, Ryan F, Swaffield JC, Johnston SA, and Moore DD (1995b): Interaction of thyroid-hormone receptor with a consereved transcriptional mediator. Nature 374: 91–94.PubMedCrossRefGoogle Scholar
  26. Liu F and Green MR (1994): Promoter targeting by adenovirus Ela through interaction with different cellular DNA-binding domains. Nature 368: 520–525.PubMedCrossRefGoogle Scholar
  27. McDonnell DP and Goldman ME (1994): Ru486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem 269: 11945–11949.PubMedGoogle Scholar
  28. McDonnell DP, Vegeto E, and O’Malley B W (1992): Identification of a negative regulatory function for steroid receptors. Proc Nat Acad Sci USA 89: 10563–10567.PubMedCrossRefGoogle Scholar
  29. McGuire WL, Chamness GC, and Fuqua SA (1991): Estrogen receptor variants in clinical breast cancer. Mol Endocrinol 5: 1571–1577.PubMedCrossRefGoogle Scholar
  30. Miesfeld R, Godowski PJ, Maler BA, and Yamamoto KR (1987): Glucocorticoid receptor mutants that define a small region sufficient for enhancer activation. Science 236: 423–427.PubMedCrossRefGoogle Scholar
  31. Meyer ME, Gronemeyer H, Turcotte B, Bocquel MT, Tasset D, and Chambon P (1989): Steroid hormone receptors compete for factors that mediate their enhancer function. Cell 57: 433–442.PubMedCrossRefGoogle Scholar
  32. Meyer ME, Quirin-Stricker C, Lerouge T, Bocquel M-T, and Gronemeyer H (1992): A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms. J Biol Chem 267: 10882–10887.PubMedGoogle Scholar
  33. Muchardt C and Yaniv M (1993): A human homologue of Saccharmyces cerevisiae SNF2/SW12 and Drosophila brm potentiates transcriptional activation by the glucocorticoid receptor. EMBO J 12: 4279–4290.PubMedGoogle Scholar
  34. Nagaya T, Madison LD, and Jameson JL (1992): Thyroid hormone receptor mutants that cause resistance to thyroid hormone: Evidence for receptor competition for DNA sequences in target genes. J Biol Chem 27: 13014–13019.Google Scholar
  35. Oakley RH, Sar M, and Cidlowski JA (1996). The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 271: 9550–9559.PubMedCrossRefGoogle Scholar
  36. Palvimo JJ, Kallio PJ, Ikonen T, M, Mehto, and Janne OA (1993): Dominant negative regulation of trans-activation by the rat androgen receptor: Roles of the N-terminal domain and heterodimer formation. Mol Endocrinol 7: 1399–1407.PubMedCrossRefGoogle Scholar
  37. Petty KJ (1995): Tissue — and cell-specific distribution of proteins that interact with the human thyroid hormone receptor-beta. Mol Cell Endocrinol 108: 131–142.PubMedCrossRefGoogle Scholar
  38. Pfaff DW and Zhu Y-S (1995): Plasticity caused by hormone actions on hypothalmic neurons. Endocrine Society Meeting, Washington, DC, S 39–43 (Abstract).Google Scholar
  39. Pfitzner E, Sak A, Ulber V, Ryffel GU, and Klein-Hitpass L (1993): Recombinant activation domains of virion protein 16 and human estrogen receptor generate transcriptional interference in vitro by distinct mechanisms. Mol Endocrinol 7: 1061–1071.PubMedCrossRefGoogle Scholar
  40. Refetoff SS, Weiss RA, and Usala SJ (1993): The syndromes of resistance to thyroid hormone. Endocrine Rev 14: 348–399.Google Scholar
  41. Saitou M, Sugal S, Tanaka T, Shimouchi K, Fuchs E, Narumiya S, and Kakizuka A (1995): Inhibition of skin development by targeted expression of a dominantnegative retinoic acid receptor. Nature 374: 159–162.PubMedCrossRefGoogle Scholar
  42. Schodin DJ, Zhuang Y, Shapiro DJ, and Katzenellenbogen BS (1995): Analysis of estrogen receptor properties that determine dominant negative effectiveness of mutant estrogen receptors. Endocrine Society, Washington, DC.Google Scholar
  43. Segars JH, Marks MS, Hirschfeld S, Differs PH, Martiniez E, Grippo JF, Wahli W, and Ozato K (1993): Inhibition of estrogen-responsive gene activation by the retinoid X receptor β: Evidence for multiple inhibitory pathways. Mol Cell Biol 13: 2258–2268.PubMedGoogle Scholar
  44. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, and Korach KS (1995): Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331: 1056–1061.CrossRefGoogle Scholar
  45. Strahle U, Boshart M, Klock G, Stewart F, and Shutz G (1989): Glucocortiocoid — and progesterone-specific effects are determined by differential expression of the respective hormone receptors. Nature 339: 629–632.PubMedCrossRefGoogle Scholar
  46. Suen CS and Chin WW (1995): A potential transcripitonal adaptor(s) may be required in thyriod hormone-stimulated transcription in vitro. Endocrinology 136: 2776–2783.PubMedCrossRefGoogle Scholar
  47. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, and Balk SP (1995): Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Eng J Med 332: 1393–1398.CrossRefGoogle Scholar
  48. Tora L, Gronemeyer H, Turcotte B, Gaub MP, and Chambon P (1988): The N-terminal regions of the chicken progesterone receptor specifies target gene activation. Nature 333: 185–188.PubMedCrossRefGoogle Scholar
  49. Tora L, White J, Brou C, Tasset D, Webster N, Scheer E, and Chambon P (1989): The human estrogen receptor has two independent non-acidic transcriptional activation functions. Cell 59: 477–487.PubMedCrossRefGoogle Scholar
  50. Truss M and Beato M (1993): Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocrine Rev 14: 459–479.Google Scholar
  51. Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, and Horwitz KB (1993): Antagonist-occupied human progesterone B receptors activate transcription without binding to progesterone response elements and are dominantly inhibated by A-receptors. Mol Endocrinol 7: 1256–1265.PubMedCrossRefGoogle Scholar
  52. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O’Malley BW, and Mc Donnell DP (1993): Human progesterone receptor A form is a cell — and promoter-specific repressor of human receptor B function. Mol Endocrinol 7: 1244–1255.PubMedCrossRefGoogle Scholar
  53. Wen DX, Xu YF, Mais DE, Goldman ME, and Mc Donnell DP (1994): The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol 14: 8356–8364.PubMedGoogle Scholar
  54. Yarwood NJ, Gurr JA, Sheppard MC, and Franklyn JA (1993): Estradiol modulates thyroid hormone regulation of the human glycoprotein hormone α subunit gene. J Biol Chem 268: 21984–21989.PubMedGoogle Scholar
  55. Yen PM and Chin WW (1994): Molecular mechanisms of dominant negative activity by nuclear hormone receptors. Mol Endocrinol 8: 1450–1454.PubMedCrossRefGoogle Scholar
  56. Yen PM, Sugawara A, Refetoff S, and Chin WW (1992): New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone. J Clin Invest 90: 1825–1831.PubMedCrossRefGoogle Scholar
  57. Yen PM, Wilcox EC, Hayashi Y, Refetoff S, and Chin WW (1995a): Studies on the repression of basal transcription (silencing) by artificial and natural thyroid hormone receptor-β mutants. Endocrinology 136: 2845–2851.PubMedCrossRefGoogle Scholar
  58. Yen PM, Wilcox EC, and Chin WW (1995b): Steroid hormone receptors selectively affect transcriptional activation but not basal repression by thyroid hormone receptors. Endocrinology 136(2): 440–445.PubMedCrossRefGoogle Scholar
  59. Yoshinaga SK, Peterson CL, Herskowitz I, and Yamamoto KR (1992): Roles of SWI1, SWI2, and SWI3 proteins for transcriptional enhancment by steroid receptors. Science 258: 1598–1604.PubMedCrossRefGoogle Scholar
  60. Zeiner M and Gehring U (1995). A protein that interacts with members of the nuclear hormone receptor family: Identification and cDNA cloning. Proc Natl Acad Sci USA 92: 11465–11469.PubMedCrossRefGoogle Scholar
  61. Zhu Y-S, Pfaff DW, Dellaverde TL, Yen PM, and Chin WW (1995): Interaction of estrogen and thyroid hormone on regulation of proenkephalon gene expressio in hypothalamus and striatum of female rats. Neuroscience Meeting, San Diego, CA. Neuroscience 189: 80–86 (Abstract).Google Scholar

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© Springer Science+Business Media New York 1997

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  • Paul M. Yen

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