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J. Biol. Chem., Vol. 282, Issue 17, 12458-12466, April 27, 2007

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Thyroid Hormone Response Element Organization Dictates the Composition of Active Receptor^*

Lara F. R. Velasco¹, Marie Togashi¹, Paul G. Walfish^¶, Rutinéia P. Pessanha, Fanny N. Moura, Gustavo B. Barra, Phuong Nguyen, Rachelle Rebong, Chaoshen Yuan, Luiz A. Simeoni, Ralff C. J. Ribeiro, John D. Baxter², Paul Webb³, and Francisco A. R. Neves⁴

From the Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brasília, DF, Brazil, the Diabetes Center and Department of Medicine, University of California, San Francisco, California 94143, and the ^¶Department of Medicine, Endocrine Division, Mount Sinai Hospital, University of Toronto Medical School, Toronto, Ontario M5G 1X5, Canada

Thyroid hormone (triiodothyronine, T₃) is known to activate transcription by binding heterodimers of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs). RXR-TRs bind to T₃ response elements (TREs) composed of direct repeats of the sequence AGGTCA spaced by four nucleotides (DR-4). In other TREs, however, the half-sites can be arranged as inverted palindromes and palindromes (Pal). Here we show that TR homodimers and monomers activate transcription from representative TREs with alternate half-site placements. TR activates transcription more efficiently than TR at an inverted palindrome (F2), and this correlates with preferential TR homodimer formation at F2 in vitro. Furthermore, reconstruction of TR transcription complexes in yeast indicates that TR homodimers are active at F2, whereas RXR-TRs are active at DR-4 and Pal. Finally, analysis of TR mutations that block homodimer and/or heterodimer formation reveal TRE-selective requirements for these surfaces in mammalian cells, which suggest that TR homodimers are active at F2, RXR-TRs at DR-4, and TR monomers at Pal. TR requires higher levels of hormone for activation at F2 than other TREs, and this differential effect is abolished by a dimer surface mutation suggesting that it is related to composition of the TR·TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo.

Received for publication, November 17, 2006 , and in revised form, February 15, 2007.

^* This work was supported by Brazilian Research Council Grants CNPq/PADCT SBIO 620003/02-2 and CNPq 40.00.43/02-5, National Institutes of Health Grants DK41482, DK51281, and DK61468 (to J. D. B.), Canadian Institutes of Health Operational Grant MOP-49448, The Mount Sinai Hospital Foundation of Toronto and Department of Medicine Research Funds, and The Julius Kuhl and Temmy Latner/Dynacare Family Foundations (to P. G. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

Deceased.

² Consultant to Karo Bio AB, a biotechnology company with commercial interests in nuclear receptors.

³ To whom correspondence may be addressed. Tel.: 415-476-6789; Fax: 415-564-5813; E-mail: pwebb{at}diabetes.ucsf.edu. ⁴ To whom correspondence may be addressed: Laboratorio de Farmacologia Molecular, Dept. de Ciências Farmacêuticas, Universidade de Brasília, Caixa Postal 4473, 70919-970, Brasília DF, Brazil. Tel.: 55-61-3072098; Fax: 55-61-3474622; E-mail: chico{at}unb.Br.

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