Transgenic targeting of a dominant negative corepressor to liver blocks basal repression by thyroid hormone receptor and increases cell proliferation

The Journal of Biological Chemistry
X FengP M Yen

Abstract

Unliganded thyroid hormone receptors (TRs) interact with corepressors and repress basal transcription of target genes in cotransfection and in vitro studies. Currently, little is known about the function of corepressors in vivo. We thus used a mouse albumin promoter to generate several transgenic mouse lines that overexpressed a dominant negative mutant corepressor, NCoRi, in liver. The transgenic mice had normal liver weight, appearance, and minimal changes in enzyme activity. To study the effects of NCoRi on transcription of hepatic target genes, we examined T3-regulated gene expression of hypo- and hyperthyroid transgenic mice. In hypothyroid mice, hepatic expression of Spot 14, Bcl-3, glucose 6-phosphatase, and 5'-deiodinase mRNA was higher in transgenic mice than littermate controls whereas these genes were induced to similar levels in T3-treated mice. Derepression was not observed for malic enzyme mRNA expression in hypothyroid mice. Thus, NCoRi selectively blocked basal transcription of several thyroid hormone-responsive genes but had no effect on ligand-mediated transcription. Additionally, compensatory increases in endogenous SMRT and NCoR mRNA were observed in hypothyroid transgenic mice. Interestingly, hepatocyte pro...Continue Reading

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