TY - JOUR T1 - Negative Regulation of Superoxide Dismutase-1 Promoter by Thyroid Hormone JF - Molecular Pharmacology JO - Mol Pharmacol SP - 793 LP - 800 DO - 10.1124/mol.106.025627 VL - 70 IS - 3 AU - Guilherme M. Santos AU - Valéry Afonso AU - Gustavo B. Barra AU - Marie Togashi AU - Paul Webb AU - Francisco A. R. Neves AU - Noureddine Lomri AU - Abderrahim Lomri Y1 - 2006/09/01 UR - http://molpharm.aspetjournals.org/content/70/3/793.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -