Negative regulation of superoxide dismutase-1 promoter by thyroid hormone.
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.
Santos
Guilherme M
GM
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 606, Lariboisiere Hospital, 2, rue Ambroise Paré, 75475 Paris Cedex 10, France.
Afonso
Valéry
V
Barra
Gustavo B
GB
Togashi
Marie
M
Webb
Paul
P
Neves
Francisco A R
FA
Lomri
Noureddine
N
Lomri
Abderrahim
A
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000235:genetics*; D017384:Sequence Deletion; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D020298:U937 Cells
D008024:Ligands; D012097:Repressor Proteins; C000606290:SOD1 protein, human; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D004247:DNA; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1