Abstract
The role of thyroid hormone [l-3,5,3′-triiodothyronine (T3)] and the thyroid hormone receptor (TR) in regulating growth, development, and metabolic homeostasis is well established. It is also emerging that T3 is associated with oxidative stress through the regulation of the activity of superoxide dismutase-1 (SOD-1), a key enzyme in the metabolism of oxygen free radicals. We found that T3 reverses the activation of the SOD-1 promoter caused by the free radical generators paraquat and phorbol 12-myristate 13-acetate through the direct repression of the SOD-1 promoter by liganded TR. Conversely, the SOD-1 promoter is significantly stimulated by unliganded TRs. This regulation requires the DNA-binding domain of the TR, which is recruited to an inhibitory element between -157 and +17 of the SOD-1 promoter. TR mutations, which abolish recruitment of coactivator proteins, block repression of the SOD-1 promoter. Conversely, a mutation that inhibits corepressor binding to the TR prevents activation. Together, our findings suggest a mechanism of negative regulation in which TR binds to the SOD-1 promoter but coactivator and corepressor binding surfaces have an inverted function. This effect may be important in T3 induction of oxidative stress in thyroid hormone excess.
Footnotes
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This work was supported in part by Ministry of Education of Brazil, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-Comité Français d'Evaluation de la Coopération Universitaire avec le Brésil program grant 434/03 (to F.A.R.N., N.L., and A.L.) and by Brazilian Research Council (Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/Programa de Apoio ao Desenvolvimento Científco e Tecnológico Subprograma de Biotecnologia 620003/02-2 and CNPq 40.00.43/02-5). G.M.S. was supported by a CAPES postdoctoral fellowship.
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F.A.R.N., N.L., and A.L. share senior authorship.
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ABBREVIATIONS: T3, l-3,5,3′-triiodothyronine; SOD, superoxide dismutase; TR, thyroid hormone receptor; TRE, thyroid hormone response element; GRIP, glucocorticoid receptor-interacting protein; SRC-1, steroid receptor coactivator-1; PMA, phorbol 12-myristate 13-acetate; GST, glutathione S-transferase; HTC, hepatoma tissue culture; DTT, dithiothreitol; SMRT, silencing mediator for retinoid and thyroid receptors; TST, Tris/saline/Tween 20; TRH, thyrotropin-releasing hormone; TSH, pituitary thyroid-stimulating hormone; DBD, DNA binding domain; wt, wild-type; RTH, resistance to thyroid hormone; F451X, deletion of helix 12; G345R, mutation in the ligand binding domain; GS125, mutation in the DBD; I280K, mutation in the corepressor binding site; GAL-4 TRβ1, chimerical TR consisting of the TRβ1LBD fused to GAL-4 DBD.
- Received April 12, 2006.
- Accepted May 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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