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Endocrine Reviews, doi:10.1210/edrv-14-2-184
Endocrine Reviews 14 (2): 184-193
Copyright © 1993 by The Endocrine Society
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*Compound via MeSH
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*LIOTHYRONINE

Thyroid Hormone Receptors: Multiple Forms, Multiple Possibilities*

MITCHELL A. LAZAR

Endocrine Division, Department of Medicine, and Department of Genetics, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104

Correspondence: Address requests for reprints to: Mitchell A. Lazar, M.D., Ph.D., University of Pennsylvania School of Medicine, 611 CRB, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104–6149.

Abstract

I. Introduction: THE biological importance of the thyroid gland has been recognized for centuries (1). The realization in the late 19th century that cretinism and myxedema result from loss of thyroid function led to the discovery of T4 (2) and T3 (3) as the predominant and most potent thyroid hormones, respectively. During the ensuing decades the plasma membrane (4), synapse (5), endoplasmic reticulum (6), and mitochondria (7) have all been considered as potential cellular sites of action of the thyroid hormones. In the 1960s, however, it was noted that many of the physiological actions of T3 were preceded by nuclear RNA transcription (8, 9), and high-affinity nuclear receptors for T3 were discovered soon thereafter (10,11). The specificity of the nuclear T3 receptors (TRs) for thyroid hormone analogs closely parallels the biological potency of the compounds (12, 13), and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T3 in most cases (14, 15). Thus, although thyroid hormones may have some important nonnuclear actions, the concept that the majority of the actions of T3 are mediated by nuclear TRs was generally accepted by the mid-1980s (16, 17). The discovery of multiple TR isoforms and the characterization of their structure, regulation, properties, and function are the subjects of this review.

Footnotes

* This work was supported by NIH Grant DK-43806, a basic research grant from Boots Pharmaceuticals, Inc., and an American Federation for Clinical Research Foundation-Merck Early Career Development Award.




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 J. Biol. Chem.Home page
N. Shibusawa, A. N. Hollenberg, and F. E. Wondisford
Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation
J. Biol. Chem., January 3, 2003; 278(2): 732 - 738.
[Abstract] [Full Text] [PDF]

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 Physiol. Rev.Home page
N. Vasudevan, S. Ogawa, and D. Pfaff
Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity
Physiol Rev, October 1, 2002; 82(4): 923 - 944.
[Abstract] [Full Text] [PDF]

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 QJMHome page
R. MALIK and H. HODGSON
The relationship between the thyroid gland and the liver
QJM, September 1, 2002; 95(9): 559 - 569.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
R. E. Weiss, C. Korcarz, O. Chassande, K. Cua, P. M. Sadow, E. Koo, J. Samarut, and R. Lang
Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor-alpha or -beta : an echocardiograph study
Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E428 - E435.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Onda, D. Li, S. Suzuki, I. Nakamura, S. Takenoshita, C.-H. Brogren, S. Stampanoni, and N. Rampino
Expansion of Microsatellite in the Thyroid Hormone Receptor-{alpha}1 Gene Linked to Increased Receptor Expression and Less Aggressive Thyroid Cancer
Clin. Cancer Res., September 1, 2002; 8(9): 2870 - 2874.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
P. E. Macchia, P. Jiang, Y.-D. Yuan, R. A. S. Chandarardna, R. E. Weiss, O. Chassande, J. Samarut, S. Refetoff, and C. F. Burant
RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor
Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E326 - E331.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
X. Li, E. A. Kimbrel, D. J. Kenan, and D. P. MCDonnell
Direct Interactions between Corepressors and Coactivators Permit the Integration of Nuclear Receptor-Mediated Repression and Activation
Mol. Endocrinol., July 1, 2002; 16(7): 1482 - 1491.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
A. Flores-Morales, H. Gullberg, L. Fernandez, N. Stahlberg, N. H. Lee, B. Vennstrom, and G. Norstedt
Patterns of Liver Gene Expression Governed by TR{beta}
Mol. Endocrinol., June 1, 2002; 16(6): 1257 - 1268.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. Incerpi, P. De Vito, P. Luly, S. Spagnuolo, and S. Leoni
Short-Term Effects of Thyroid Hormones and 3,5-Diiodothyronine on Membrane Transport Systems in Chick Embryo Hepatocytes
Endocrinology, May 1, 2002; 143(5): 1660 - 1668.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
J. M. Weitzel, C. Radtke, and H. J. Seitz
Two thyroid hormone-mediated gene expression patterns in vivo identified by cDNA expression arrays in rat
Nucleic Acids Res., December 15, 2001; 29(24): 5148 - 5155.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
K. L. Sunn, T.-A. Cock, L. A. Crofts, J. A. Eisman, and E. M. Gardiner
Novel N-Terminal Variant of Human VDR
Mol. Endocrinol., September 1, 2001; 15(9): 1599 - 1609.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
T. Ishizuka, T. Satoh, T. Monden, N. Shibusawa, T. Hashida, M. Yamada, and M. Mori
Human Immunodeficiency Virus Type 1 Tat Binding Protein-1 Is a Transcriptional Coactivator Specific for TR
Mol. Endocrinol., August 1, 2001; 15(8): 1329 - 1343.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
K. Gauthier, M. Plateroti, C. B. Harvey, G. R. Williams, R. E. Weiss, S. Refetoff, J. F. Willott, V. Sundin, J.-P. Roux, L. Malaval, et al.
Genetic Analysis Reveals Different Functions for the Products of the Thyroid Hormone Receptor {alpha} Locus
Mol. Cell. Biol., July 15, 2001; 21(14): 4748 - 4760.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
M. Plateroti, K. Gauthier, C. Domon-Dell, J.-N. Freund, J. Samarut, and O. Chassande
Functional Interference between Thyroid Hormone Receptor {alpha} (TR{alpha}) and Natural Truncated TR{Delta}{alpha} Isoforms in the Control of Intestine Development
Mol. Cell. Biol., July 15, 2001; 21(14): 4761 - 4772.
[Abstract] [Full Text] [PDF]

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 Annals of Clinical & Laboratory ScienceHome page
W. E. Winter and M. R. Signorino
Molecular Thyroidology
Ann. Clin. Lab. Sci., July 1, 2001; 31(3): 221 - 244.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. R. Yudt and J. A. Cidlowski
Molecular Identification and Characterization of A and B Forms of the Glucocorticoid Receptor
Mol. Endocrinol., July 1, 2001; 15(7): 1093 - 1103.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
Z. Yang and M. L. Privalsky
Isoform-Specific Transcriptional Regulation by Thyroid Hormone Receptors: Hormone-Independent Activation Operates through a Steroid Receptor Mode of Coactivator Interaction
Mol. Endocrinol., July 1, 2001; 15(7): 1170 - 1185.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
G. d’Amati, C. R. T. di Gioia, D. Mentuccia, D. Pistilli, L. Proietti-Pannunzi, F. Miraldi, P. Gallo, and F. S. Celi
Increased Expression of Thyroid Hormone Receptor Isoforms in End-Stage Human Congestive Heart Failure
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2080 - 2084.
[Abstract] [Full Text]

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 FASEB J.Home page
M. PIBIRI, G. M. LEDDA-COLUMBANO, C. COSSU, G. SIMBULA, M. MENEGAZZI, H. SHINOZUKA, and A. COLUMBANO
Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3)
FASEB J, April 1, 2001; 15(6): 1006 - 1013.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
R. L. Wagner, B. R. Huber, A. K. Shiau, A. Kelly, S. T. Cunha Lima, T. S. Scanlan, J. W. Apriletti, J. D. Baxter, B. L. West, and R. J. Fletterick
Hormone Selectivity in Thyroid Hormone Receptors
Mol. Endocrinol., March 1, 2001; 15(3): 398 - 410.
[Abstract] [Full Text]

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 CirculationHome page
K. Kinugawa, W. A. Minobe, W. M. Wood, E. C. Ridgway, J. D. Baxter, R. C. J. Ribeiro, M. F. Tawadrous, B. A. Lowes, C. S. Long, and M. R. Bristow
Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart : Evidence for Altered Thyroid Hormone Receptor Gene Expression
Circulation, February 27, 2001; 103(8): 1089 - 1094.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. R. Manna, J. Kero, M. Tena-Sempere, P. Pakarinen, D. M. Stocco, and I. T. Huhtaniemi
Assessment of Mechanisms of Thyroid Hormone Action in Mouse Leydig Cells: Regulation of the Steroidogenic Acute Regulatory Protein, Steroidogenesis, and Luteinizing Hormone Receptor Function
Endocrinology, January 1, 2001; 142(1): 319 - 331.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. L. S. Dowling, E. A. Iannacone, and R. T. Zoeller
Maternal Hypothyroidism Selectively Affects the Expression of Neuroendocrine-Specific Protein A Messenger Ribonucleic Acid in the Proliferative Zone of the Fetal Rat Brain Cortex
Endocrinology, January 1, 2001; 142(1): 390 - 399.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
Q.-L. Li, E. Jansen, G. A. Brent, and T. C. Friedman
Regulation of prohormone convertase 1 (PC1) by thyroid hormone
Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E160 - E170.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
P. Webb, C. M. Anderson, C. Valentine, P. Nguyen, A. Marimuthu, B. L. West, J. D. Baxter, and P. J. Kushner
The Nuclear Receptor Corepressor (N-CoR) Contains Three Isoleucine Motifs (I/LXXII) That Serve as Receptor Interaction Domains (IDs)
Mol. Endocrinol., December 1, 2000; 14(12): 1976 - 1985.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
D. Sharma and J. D. Fondell
Temporal Formation of Distinct Thyroid Hormone Receptor Coactivator Complexes in HeLa Cells
Mol. Endocrinol., December 1, 2000; 14(12): 2001 - 2009.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
G. R. Williams
Cloning and Characterization of Two Novel Thyroid Hormone Receptor beta Isoforms
Mol. Cell. Biol., November 15, 2000; 20(22): 8329 - 8342.
[Abstract] [Full Text]

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 EndocrinologyHome page
A. Menendez-Hurtado, A. Santos, and A. Perez-Castillo
Characterization of the Promoter Region of the Rat CCAAT/Enhancer-Binding Protein {alpha} Gene and Regulation by Thyroid Hormone in Rat Immortalized Brown Adipocytes
Endocrinology, November 1, 2000; 141(11): 4164 - 4170.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
H. Robson, T. Siebler, D. A. Stevens, S. M. Shalet, and G. R. Williams
Thyroid Hormone Acts Directly on Growth Plate Chondrocytes to Promote Hypertrophic Differentiation and Inhibit Clonal Expansion and Cell Proliferation
Endocrinology, October 1, 2000; 141(10): 3887 - 3897.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
M. Katsumata, D. Cattaneo, P. White, K. A. Burton, and M. J. Dauncey
Growth Hormone Receptor Gene Expression in Porcine Skeletal and Cardiac Muscles Is Selectively Regulated by Postnatal Undernutrition
J. Nutr., October 1, 2000; 130(10): 2482 - 2488.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
E. A. Jannini, A. Crescenzi, N. Rucci, E. Screponi, E. Carosa, A. De Matteis, E. Macchia, G. d’Amati, and M. D’Armiento
Ontogenetic Pattern of Thyroid Hormone Receptor Expression in the Human Testis
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3453 - 3457.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
S.-H. Hong and M. L. Privalsky
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., September 1, 2000; 20(17): 6612 - 6625.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
H. Favre-Young, F. Dif, F. Roussille, B. A. Demeneix, P. A. Kelly, M. Edery, and A. de Luze
Cross-Talk between Signal Transducer and Activator of Transcription (Stat5) and Thyroid Hormone Receptor-{beta} 1 (TR{beta}1) Signaling Pathways
Mol. Endocrinol., September 1, 2000; 14(9): 1411 - 1424.
[Abstract] [Full Text]

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 EndocrinologyHome page
M. A. Lazar
Editorial: A Sweetheart Deal for Thyroid Hormone
Endocrinology, September 1, 2000; 141(9): 3055 - 3056.
[Full Text] [PDF]


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