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Accelerated Communication

Negative Regulation of Superoxide Dismutase-1 Promoter by Thyroid Hormone

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 606, Lariboisière Hospital, and University of Paris, Paris, France (G.M.S., V.A., A.L.); Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom (G.M.S.); Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brasilia, Brazil (G.B.B., M.T., F.A.R.N.); Diabetes Center and Department of Medicine, University of California School of Medicine, San Francisco, California (M.T., P.W.); and University of Cergy-Pontoise, Unité de Formation et de Recherche des Sciences et Techniques, GRP2H-INSERM Unité 680, Département de Biologie, Cergy-Pontoise, France (G.M.S., N.L.)

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.

Address correspondence to: Abderrahim Lomri, INSERM Unité 606, Lariboisiere Hospital, 2, rue Ambroise Paré, 75475 Paris Cedex 10, France. E-mail: lomri{at}larib.inserm.fr

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