Negative Regulation of Superoxide Dismutase-1 Promoter by Thyroid Hormone

• Published in: Molecular pharmacology 2006-09, Vol.70 (3), p.793-800
• Main Authors: Santos, Guilherme M, Afonso, Valéry, Barra, Gustavo B, Togashi, Marie, Webb, Paul, Neves, Francisco A R, Lomri, Noureddine, Lomri, Abderrahim
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding Sites; Cells, Cultured; DNA - metabolism; Down-Regulation - drug effects; Humans; Ligands; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Rats; Repressor Proteins - metabolism; Response Elements - drug effects; Response Elements - genetics; Sequence Deletion; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Thyroid Hormone Receptors beta - metabolism; Triiodothyronine - pharmacology; U937 Cells
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.106.025627

The role of thyroid hormone [ l -3,5,3′-triiodothyronine (T 3 )] and the thyroid hormone receptor (TR) in regulating growth, development, and metabolic homeostasis is well established. It is also emerging that T 3 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 T 3 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 T 3 induction of oxidative stress in thyroid hormone excess.