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First published on May 31, 2006; DOI: 10.1124/mol.106.025627

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Received for publication April 12, 2006.
Revised May 15, 2006.
Accepted for publication May 30, 2006.

Negative regulation of superoxide dismutase-1 promoter by thyroid hormone

Guilherme M Santos 1, Valery Afonso 2, Gustavo Barra 3, Marie Togashi 4, Paul Webb 5, Francisco AR Neves 3, Noureddine Lomri 6, Abderrahim Lomri 2*

1 MRC-LMB, Cambridge/INSERM Unite 606 2 INSERM Unite 606, France 3 University of Brasilia, Brazil 4 University of California/University of Brasilia, Brazil 5 University of California 6 University of Cergy-Pontoise, France

* Address correspondence to: E-mail: lomri{at}larib.inserm.fr

Abstract

The role of thyroid hormone (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 PMA, 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 co- activator proteins, block repression of the SOD-1 promoter. Conversely a mutation, which inhibits co- repressor 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 co-activator and co-repressor binding surfaces have an inverted function. This effect may be important in T3 induction of oxidative stress in thyroid hormone excess.


Key words: Thyroid hormone, Receptor binding studies, Regulation of gene expression, Regulation - transcriptional, Oxidative stress/antioxidants


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