This Article Full Text Full Text (PDF) All Versions of this Article: 17/5/895    most recent Author Manuscript (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 NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, H. Articles by Cheng, S.-Y. Search for Related Content PubMed PubMed Citation Articles by Suzuki, H. Articles by Cheng, S.-Y.

Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor ß in Mice by the Ablation of One Wild-Type ß Allele

Laboratory of Molecular Biology (H.S., X.-Y.Z., S.-Y.C.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264; Department of Human Genetics (D.F.), Mount Sinai School of Medicine, New York, New York 10029; and Department of Pathology (M.C.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Dr. S.-Y. Cheng, Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

Mutations in the thyroid hormone receptor (TR) ß gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRß mutation (TRßPV) with mice carrying a TRß null mutation (TRß^-/-) to determine the consequences of the TRßPV mutation in the absence of wild-type TRß. TRß^PV/- mice are distinct from TRß^+/- mice that did not show abnormalities in thyroid function tests. TRß^PV/- mice are also distinct from TRß^PV/+ and TRß^-/- mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRß^PV/PV mice. Similar to TRß^PV/PV mice, TRß^PV/- mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T₃-target genes in the tissues of TRß^PV/- and TRß^PV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TR1 for binding to thyroid hormone response elements in TRß^PV/- mice as effectively as in TRß^PV/PV mice. Thus, the actions of mutant TRß are markedly potentiated by the ablation of the second TRß allele, suggesting that interference with wild-type TR1-mediated gene regulation by mutant TRß leads to severe RTH.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

This article has been cited by other articles:

				P.-J. Tai, Y.-H. Huang, C.-H. Shih, R.-N. Chen, C.-D. Chen, W.-J. Chen, C.-S. Wang, and K.-H. Lin Direct Regulation of Androgen Receptor-Associated Protein 70 by Thyroid Hormone and Its Receptors Endocrinology, July 1, 2007; 148(7): 3485 - 3495. [Abstract] [Full Text] [PDF]

				Genetically Modified Animals in Endocrinology Endocr. Rev., December 1, 2005; 26(7): 985 - 993. [Abstract] [Full Text] [PDF]

				H. Ying, F. Furuya, M. C. Willingham, J. Xu, B. W. O'Malley, and S.-y. Cheng Dual Functions of the Steroid Hormone Receptor Coactivator 3 in Modulating Resistance to Thyroid Hormone Mol. Cell. Biol., September 1, 2005; 25(17): 7687 - 7695. [Abstract] [Full Text] [PDF]

				Y. Kato, H. Ying, M. C. Willingham, and S.-Y. Cheng A Tumor Suppressor Role for Thyroid Hormone {beta} Receptor in a Mouse Model of Thyroid Carcinogenesis Endocrinology, October 1, 2004; 145(10): 4430 - 4438. [Abstract] [Full Text] [PDF]

				S. M. Dupre, H. Guissouma, F. Flamant, I. Seugnet, T. S. Scanlan, J. D. Baxter, J. Samarut, B. A. Demeneix, and N. Becker Both Thyroid Hormone Receptor (TR){beta}1 and TR{beta}2 Isoforms Contribute to the Regulation of Hypothalamic Thyrotropin-Releasing Hormone Endocrinology, May 1, 2004; 145(5): 2337 - 2345. [Abstract] [Full Text] [PDF]

				H. Suzuki and S.-y. Cheng Compensatory Role of Thyroid Hormone Receptor (TR){alpha}1 in Resistance to Thyroid Hormone: Study in Mice with a Targeted Mutation in the TR{beta} Gene and Deficient in TR{alpha}1 Mol. Endocrinol., August 1, 2003; 17(8): 1647 - 1655. [Abstract] [Full Text] [PDF]