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

X Feng1, Y Jiang, P Meltzer

  • 1Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|May 1, 2001
PubMed

Insights

Thyroid hormone receptors (TRs) use corepressors to control gene activity. This study shows that blocking a corepressor (NCoRi) in mice disrupts basal gene transcription and increases liver cell proliferation.

Area of Science:

  • Molecular Endocrinology
  • Gene Regulation
  • Hepatocyte Biology

Background:

  • Unliganded thyroid hormone receptors (TRs) interact with corepressors to repress gene transcription.
  • The in vivo function of corepressors, particularly in the liver, remains largely uncharacterized.

Purpose of the Study:

  • To investigate the in vivo role of corepressors in regulating hepatic gene transcription and cellular processes.
  • To determine the effect of overexpressing a dominant-negative corepressor mutant (NCoRi) on thyroid hormone-responsive genes and hepatocyte proliferation in mice.

Main Methods:

  • Generation of transgenic mice overexpressing a dominant-negative NCoRi mutant in the liver using a mouse albumin promoter.
  • Analysis of thyroid hormone-regulated gene expression in hypothyroid and hyperthyroid transgenic mice.
  • Assessment of hepatocyte proliferation using BrdUrd incorporation and gene expression profiling via cDNA microarray.

Main Results:

  • NCoRi overexpression selectively blocked basal transcription of several thyroid hormone-responsive genes (Spot 14, Bcl-3, glucose 6-phosphatase, 5'-deiodinase) in hypothyroid mice.
  • Ligand-mediated transcription (T3-induced) of these genes was unaffected by NCoRi.
  • Increased hepatocyte proliferation and induction of cell proliferation-related genes were observed in NCoRi transgenic mice, with compensatory increases in endogenous corepressor mRNA.

Conclusions:

  • Corepressor NCoR plays a critical role in mediating basal transcriptional repression by TRs in vivo.
  • Inhibition of NCoR function leads to derepression of target genes and promotes hepatocyte proliferation, suggesting a role in preventing uncontrolled cell growth.

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