This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoh, S. M. Articles by Privalsky, M. L. Search for Related Content PubMed PubMed Citation Articles by Yoh, S. M. Articles by Privalsky, M. L.

Thyroid Hormone Resistance Syndrome Manifests as an Aberrant Interaction between Mutant T₃ Receptors and Transcriptional Corepressors

Section of Microbiology (S.M.Y., M.L.P.) Division of Biological Sciences University of California at Davis Davis, California 95616
Department of Medicine (V.K.K.C.) University of Cambridge Level 5, Addenbrooke’s Hospital Cambridge, CB2 2QQ, United Kingdom

Nuclear hormone receptors are hormone-regulated transcription factors that play critical roles in chordate development and homeostasis. Aberrant nuclear hormone receptors have been implicated as causal agents in a number of endocrine and neoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a human genetic disease characterized by an impaired physiological response to thyroid hormone. RTH is associated with diverse mutations in the thyroid hormone receptor ß-gene. The resulting mutant receptors function as dominant negatives, interfering with the actions of normal thyroid hormone receptors coexpressed in the same cells. We report here that RTH receptors interact aberrantly with a newly recognized family of transcriptional corepressors variously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor interacting protein-13 (RIP-13), silencing mediator for retinoid and thyroid hormone receptors (SMRT), and thyroid hormone receptor-associating cofactor (TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from corepressors in the presence of thyroid hormone. Two of the RTH mutations uncouple corepressor dissociation from hormone binding; two additional RTH mutants exhibit an unusually strong interaction with corepressor under all hormone conditions tested. Finally, artificial mutants that abolish corepressor binding abrogate the dominant negative activity of RTH mutants. We suggest that an altered corepressor interaction is likely to play a critical role in the dominant negative potency of RTH mutants and may contribute to the variable phenotype in this disorder.

This article has been cited by other articles:

				N K Agrawal, R Goyal, A Rastogi, D Naik, and S K Singh Thyroid hormone resistance Postgrad. Med. J., September 1, 2008; 84(995): 473 - 477. [Abstract] [Full Text] [PDF]

				R. Rouf, S. Greytak, E. C. Wooten, J. Wu, J. Boltax, M. Picard, E. C. Svensson, W. H. Dillmann, R. D. Patten, and G. S. Huggins Increased FOG-2 in Failing Myocardium Disrupts Thyroid Hormone-Dependent SERCA2 Gene Transcription Circ. Res., August 29, 2008; 103(5): 493 - 501. [Abstract] [Full Text] [PDF]

				C. B. Harvey, J. H. D. Bassett, P. Maruvada, P. M. Yen, and G. R. Williams The Rat Thyroid Hormone Receptor (TR) {Delta}{beta}3 Displays Cell-, TR Isoform-, and Thyroid Hormone Response Element-Specific Actions Endocrinology, April 1, 2007; 148(4): 1764 - 1773. [Abstract] [Full Text] [PDF]

				S. Mamanasiri, S. Yesil, A. M. Dumitrescu, X.-H. Liao, T. Demir, R. E. Weiss, and S. Refetoff Mosaicism of a Thyroid Hormone Receptor-{beta} Gene Mutation in Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3471 - 3477. [Abstract] [Full Text] [PDF]

				S. Y. Wu, R. N. Cohen, E. Simsek, D. A. Senses, N. E. Yar, H. Grasberger, J. Noel, S. Refetoff, and R. E. Weiss A Novel Thyroid Hormone Receptor-{beta} Mutation That Fails to Bind Nuclear Receptor Corepressor in a Patient as an Apparent Cause of Severe, Predominantly Pituitary Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1887 - 1895. [Abstract] [Full Text] [PDF]

				A. Y. M. Au, C. McBride, K. G. Wilhelm Jr., R. J. Koenig, B. Speller, L. Cheung, M. Messina, J. Wentworth, V. Tasevski, D. Learoyd, et al. PAX8-Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Disrupts Normal PAX8 or PPAR{gamma} Transcriptional Function and Stimulates Follicular Thyroid Cell Growth Endocrinology, January 1, 2006; 147(1): 367 - 376. [Abstract] [Full Text] [PDF]

				O. Araki, H. Ying, F. Furuya, X. Zhu, and S.-y. Cheng Thyroid hormone receptor {beta} mutants: Dominant negative regulators of peroxisome proliferator-activated receptor {gamma} action PNAS, November 8, 2005; 102(45): 16251 - 16256. [Abstract] [Full Text] [PDF]

				T. Ishizuka and M. A. Lazar The Nuclear Receptor Corepressor Deacetylase Activating Domain Is Essential for Repression by Thyroid Hormone Receptor Mol. Endocrinol., June 1, 2005; 19(6): 1443 - 1451. [Abstract] [Full Text] [PDF]

				W. Wan, B. Farboud, and M. L. Privalsky Pituitary Resistance to Thyroid Hormone Syndrome Is Associated with T3 Receptor Mutants that Selectively Impair {beta}2 Isoform Function Mol. Endocrinol., June 1, 2005; 19(6): 1529 - 1542. [Abstract] [Full Text] [PDF]

				R. Kumar, A. E. Gururaj, R. K. Vadlamudi, and S. K. Rayala The Clinical Relevance of Steroid Hormone Receptor Corepressors Clin. Cancer Res., April 15, 2005; 11(8): 2822 - 2831. [Abstract] [Full Text] [PDF]

				S. Lee and M. L. Privalsky Heterodimers of Retinoic Acid Receptors and Thyroid Hormone Receptors Display Unique Combinatorial Regulatory Properties Mol. Endocrinol., April 1, 2005; 19(4): 863 - 878. [Abstract] [Full Text] [PDF]

				M. L. Goodson, B. A. Jonas, and M. L. Privalsky Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors J. Biol. Chem., March 4, 2005; 280(9): 7493 - 7503. [Abstract] [Full Text] [PDF]

				J. Lado-Abeal, A. M. Dumitrescu, X.-H. Liao, R. N. Cohen, J. Pohlenz, R. E. Weiss, M.-C. Lebrethon, A. Verloes, and S. Refetoff A De Novo Mutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor {beta} Gene Perpetuates Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1760 - 1767. [Abstract] [Full Text] [PDF]

				K. Kawai, S. Sasaki, H. Morita, T. Ito, S. Suzuki, H. Misawa, and H. Nakamura Unliganded Thyroid Hormone Receptor-{beta}1 Represses Liver X Receptor {alpha}/Oxysterol-Dependent Transactivation Endocrinology, December 1, 2004; 145(12): 5515 - 5524. [Abstract] [Full Text] [PDF]

				M. Akaike, W. Che, N.-L. Marmarosh, S. Ohta, M. Osawa, B. Ding, B. C. Berk, C. Yan, and J.-i. Abe The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor {gamma}1 (PPAR{gamma}1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPAR{gamma}1 Transcriptional Activation: Involvement in Flow-Induced PPAR{gamma} Activation in Endothelial Cells Mol. Cell. Biol., October 1, 2004; 24(19): 8691 - 8704. [Abstract] [Full Text] [PDF]

				M. Malartre, S. Short, and C. Sharpe Alternative splicing generates multiple SMRT transcripts encoding conserved repressor domains linked to variable transcription factor interaction domains Nucleic Acids Res., September 1, 2004; 32(15): 4676 - 4686. [Abstract] [Full Text] [PDF]

				M. Agostini, M. Gurnell, D. B. Savage, E. M. Wood, A. G. Smith, O. Rajanayagam, K. T. Garnes, S. H. Levinson, H. E. Xu, J. W. R. Schwabe, et al. Tyrosine Agonists Reverse the Molecular Defects Associated with Dominant-Negative Mutations in Human Peroxisome Proliferator-Activated Receptor {gamma} Endocrinology, April 1, 2004; 145(4): 1527 - 1538. [Abstract] [Full Text] [PDF]

				B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression Mol. Cell. Biol., April 15, 2003; 23(8): 2844 - 2858. [Abstract] [Full Text] [PDF]

				K. Jepsen and M. G. Rosenfeld Biological roles and mechanistic actions of co-repressor complexes J. Cell Sci., February 15, 2002; 115(4): 689 - 698. [Abstract] [Full Text] [PDF]

				A. Marimuthu, W. Feng, T. Tagami, H. Nguyen, J. L. Jameson, R. J. Fletterick, J. D. Baxter, and B. L. West TR Surfaces and Conformations Required to Bind Nuclear Receptor Corepressor Mol. Endocrinol., February 1, 2002; 16(2): 271 - 286. [Abstract] [Full Text] [PDF]

				S. A. Phillips, P. Rotman-Pikielny, J. Lazar, S. Ando, P. Hauser, M. C. Skarulis, F. Brucker-Davis, and P. M. Yen Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5142 - 5147. [Abstract] [Full Text] [PDF]

				P. M. Yen Physiological and Molecular Basis of Thyroid Hormone Action Physiol Rev, July 1, 2001; 81(3): 1097 - 1142. [Abstract] [Full Text] [PDF]

				A. Aranda and A. Pascual Nuclear Hormone Receptors and Gene Expression Physiol Rev, July 1, 2001; 81(3): 1269 - 1304. [Abstract] [Full Text] [PDF]

				K.-h. Lin and Y.-h. Wu shen-liang chen Impaired Interaction of Mutant Thyroid Hormone Receptors Associated with Human Hepatocellular Carcinoma with Transcriptional Coregulators Endocrinology, February 1, 2001; 142(2): 653 - 662. [Abstract] [Full Text] [PDF]

				S. Reutrakul, P. M. Sadow, S. Pannain, J. Pohlenz, G. A. Carvalho, P. E. Macchia, R. E. Weiss, and S. Refetoff Search for Abnormalities of Nuclear Corepressors, Coactivators, and a Coregulator in Families with Resistance to Thyroid Hormone without Mutations in Thyroid Hormone Receptor {beta} or {alpha} Genes J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3609 - 3617. [Abstract] [Full Text]

				L. J. BURKE and A. BANIAHMAD Co-repressors 2000 FASEB J, October 1, 2000; 14(13): 1876 - 1888. [Abstract] [Full Text]

				A. Antebi, W.-H. Yeh, D. Tait, E. M. Hedgecock, and D. L. Riddle daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans Genes & Dev., June 15, 2000; 14(12): 1512 - 1527. [Abstract] [Full Text]

				R. N. Cohen, A. Putney, F. E. Wondisford, and A. N. Hollenberg The Nuclear Corepressors Recognize Distinct Nuclear Receptor Complexes Mol. Endocrinol., June 1, 2000; 14(6): 900 - 914. [Abstract] [Full Text]

				S. Ercan-Fang, H. L. Schwartz, C. N. Mariash, and J. H. Oppenheimer Quantitative Assessment of Pituitary Resistance to Thyroid Hormone from Plots of the Logarithm of Thyrotropin Versus Serum Free Thyroxine Index J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2299 - 2303. [Abstract] [Full Text]

				B. Altincicek, S. P. Tenbaum, U. Dressel, D. Thormeyer, R. Renkawitz, and A. Baniahmad Interaction of the Corepressor Alien with DAX-1 Is Abrogated by Mutations of DAX-1 Involved in Adrenal Hypoplasia Congenita J. Biol. Chem., March 10, 2000; 275(11): 7662 - 7667. [Abstract] [Full Text] [PDF]

				M. Gurnell, J. M. Wentworth, M. Agostini, M. Adams, T. N. Collingwood, C. Provenzano, P. O. Browne, O. Rajanayagam, T. P. Burris, J. W. Schwabe, et al. A Dominant-negative Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Mutant Is a Constitutive Repressor and Inhibits PPARgamma -mediated Adipogenesis J. Biol. Chem., February 25, 2000; 275(8): 5754 - 5759. [Abstract] [Full Text] [PDF]

				C. K. Glass and M. G. Rosenfeld The coregulator exchange in transcriptional functions of nuclear receptors Genes & Dev., January 15, 2000; 14(2): 121 - 141. [Full Text]

				E. Y. Huang, J. Zhang, E. A. Miska, M. G. Guenther, T. Kouzarides, and M. A. Lazar Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway Genes & Dev., January 1, 2000; 14(1): 45 - 54. [Abstract] [Full Text]

				Z. Yang, S.-H. Hong, and M. L. Privalsky Transcriptional Anti-repression. THYROID HORMONE RECEPTOR beta -2 RECRUITS SMRT COREPRESSOR BUT INTERFERES WITH SUBSEQUENT ASSEMBLY OF A FUNCTIONAL COREPRESSOR COMPLEX J. Biol. Chem., December 24, 1999; 274(52): 37131 - 37138. [Abstract] [Full Text] [PDF]

				P.-Y. Chien, M. Ito, Y. Park, T. Tagami, B. D. Gehm, and J. L. Jameson A Fusion Protein of the Estrogen Receptor (ER) and Nuclear Receptor Corepressor (NCoR) Strongly Inhibits Estrogen-Dependent Responses in Breast Cancer Cells Mol. Endocrinol., December 1, 1999; 13(12): 2122 - 2136. [Abstract] [Full Text]

				J. Pohlenz, R. E. Weiss, P. E. Macchia, S. Pannain, I. T. Lau, H. Ho, and S. Refetoff Five New Families with Resistance to Thyroid Hormone not Caused by Mutations in the Thyroid Hormone Receptor {beta} Gene J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3919 - 3928. [Abstract] [Full Text]

				N. J. McKenna, R. B. Lanz, and B. W. O’Malley Nuclear Receptor Coregulators: Cellular and Molecular Biology Endocr. Rev., June 1, 1999; 20(3): 321 - 344. [Abstract] [Full Text]

				S. M. Thacher, S. Nagpal, E. S. Klein, T. Arefieg, G. Krasinski, D. DiSepio, C. Agarwal, A. Johnson, R. L. Eckert, and R. A. S. Chandraratna Cell Type and Gene-specific Activity of the Retinoid Inverse Agonist AGN 193109: Divergent Effects from Agonist at Retinoic Acid Receptor {{gamma}} in Human Keratinocytes Cell Growth Differ., April 1, 1999; 10(4): 255 - 262. [Abstract] [Full Text]

				R. E. Weiss and S. Refetoff Editorial: Treatment of Resistance to Thyroid Hormone--Primum Non Nocere J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 401 - 404. [Full Text]

				C. J. McCabe, N. J. Gittoes, M. C. Sheppard, and J. A. Franklyn Thyroid Receptor {alpha}1 and {alpha}2 Mutations in Nonfunctioning Pituitary Tumors J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 649 - 653. [Abstract] [Full Text]

				S.-H. Hong and M. L. Privalsky Retinoid Isomers Differ in the Ability to Induce Release of SMRT Corepressor from Retinoic Acid Receptor-alpha J. Biol. Chem., January 29, 1999; 274(5): 2885 - 2892. [Abstract] [Full Text] [PDF]

				T. Tagami, W.-X. Gu, P. T. Peairs, B. L. West, and J. L. Jameson A Novel Natural Mutation in the Thyroid Hormone Receptor Defines a Dual Functional Domain That Exchanges Nuclear Receptor Corepressors and Coactivators Mol. Endocrinol., December 1, 1998; 12(12): 1888 - 1902. [Abstract] [Full Text]

				J. D. Safer, R. N. Cohen, A. N. Hollenberg, and F. E. Wondisford Defective Release of Corepressor by Hinge Mutants of the Thyroid Hormone Receptor Found in Patients with Resistance to Thyroid Hormone J. Biol. Chem., November 13, 1998; 273(46): 30175 - 30182. [Abstract] [Full Text] [PDF]

				C.-W. Wong and M. L. Privalsky Components of the SMRT Corepressor Complex Exhibit Distinctive Interactions with the POZ Domain Oncoproteins PLZF, PLZF-RARalpha , and BCL-6 J. Biol. Chem., October 16, 1998; 273(42): 27695 - 27702. [Abstract] [Full Text] [PDF]

				C.-W. Wong and M. L. Privalsky Transcriptional Silencing Is Defined by Isoform- and Heterodimer-Specific Interactions between Nuclear Hormone Receptors and Corepressors Mol. Cell. Biol., October 1, 1998; 18(10): 5724 - 5733. [Abstract] [Full Text]

				Y. Liu, A. Takeshita, S. Misiti, W. W. Chin, and P. M. Yen Lack of Coactivator Interaction Can Be a Mechanism for Dominant Negative Activity by Mutant Thyroid Hormone Receptors Endocrinology, October 1, 1998; 139(10): 4197 - 4204. [Abstract] [Full Text] [PDF]

				S.-H. Hong, C.-W. Wong, and M. L. Privalsky 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., August 1, 1998; 12(8): 1161 - 1171. [Abstract] [Full Text]

				M. Yamaguchi, M. Nakamoto, H. Honda, T. Nakagawa, H. Fujita, T. Nakamura, H. Hirai, S. Narumiya, and A. Kakizuka Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells PNAS, June 23, 1998; 95(13): 7491 - 7496. [Abstract] [Full Text] [PDF]

				R. J. Clifton-Bligh, F. de Zegher, R. L. Wagner, T. N. Collingwood, I. Francois, M. Van Helvoirt, R. J. Fletterick, and V. K. K. Chatterjee A Novel TR{beta} Mutation (R383H) in Resistance to Thyroid Hormone Syndrome Predominantly Impairs Corepressor Release and Negative Transcriptional Regulation Mol. Endocrinol., May 1, 1998; 12(5): 609 - 621. [Abstract] [Full Text]

				T. Tagami, P. Kopp, W. Johnson, O. K. Arseven, and J. L. Jameson The Thyroid Hormone Receptor Variant {alpha}2 Is a Weak Antagonist because It Is Deficient in Interactions with Nuclear Receptor Corepressors Endocrinology, May 1, 1998; 139(5): 2535 - 2544. [Abstract] [Full Text] [PDF]

				A. Baniahmad, U. Dressel, and R. Renkawitz Cell-Specific Inhibition of Retinoic Acid Receptor-{alpha} Silencing by the AF2/{tau}c Activation Domain Can Be Overcome by the Corepressor SMRT, But Not by N-CoR Mol. Endocrinol., April 1, 1998; 12(4): 504 - 512. [Abstract] [Full Text]

				T. Tagami and J. L. Jameson Nuclear Corepressors Enhance the Dominant Negative Activity of Mutant Receptors That Cause Resistance to Thyroid Hormone Endocrinology, February 1, 1998; 139(2): 640 - 650. [Abstract] [Full Text] [PDF]

				S.-H. Hong, G. David, C.-W. Wong, A. Dejean, and M. L. Privalsky SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha  (RARalpha ) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia PNAS, August 19, 1997; 94(17): 9028 - 9033. [Abstract] [Full Text] [PDF]

				S. M. Yoh and M. L. Privalsky Transcriptional Repression by Thyroid Hormone Receptors. A ROLE FOR RECEPTOR HOMODIMERS IN THE RECRUITMENT OF SMRT COREPRESSOR J. Biol. Chem., May 11, 2001; 276(20): 16857 - 16867. [Abstract] [Full Text] [PDF]

				C. T. Baumann, P. Maruvada, G. L. Hager, and P. M. Yen Nuclear Cytoplasmic Shuttling by Thyroid Hormone Receptors. MULTIPLE PROTEIN INTERACTIONS ARE REQUIRED FOR NUCLEAR RETENTION J. Biol. Chem., March 30, 2001; 276(14): 11237 - 11245. [Abstract] [Full Text] [PDF]

				D.-J. Jung, S.-K. Lee, and J. W. Lee Agonist-dependent Repression Mediated by Mutant Estrogen Receptor alpha That Lacks the Activation Function 2 Core Domain J. Biol. Chem., September 28, 2001; 276(40): 37280 - 37283. [Abstract] [Full Text] [PDF]

				M. G. Rosenfeld and C. K. Glass Coregulator Codes of Transcriptional Regulation by Nuclear Receptors J. Biol. Chem., September 28, 2001; 276(40): 36865 - 36868. [Full Text] [PDF]