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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)

Laura Fozzatti1, Changxue Lu, Dong Wook Kim

  • 1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 12, 2011
PubMed

Insights

Thyroid hormone resistance (RTH) is caused by thyroid hormone receptor beta (TRβ) mutations. This study shows that blocking corepressor interaction corrects RTH in mice, suggesting new therapeutic targets.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the thyroid hormone receptor beta (TRβ) ligand-binding domain cause resistance to thyroid hormone (RTH).
  • TRβ mutants inhibit wild-type TRs, disrupting the pituitary-thyroid axis and causing peripheral tissue resistance.
  • The dominant-negative effect is hypothesized to stem from impaired release of nuclear corepressors (NCORs).

Purpose of the Study:

  • To investigate the in vivo role of nuclear corepressor 1 (NCOR1) in the pathogenesis of RTH.
  • To determine if disrupting the TRβ-NCOR1 interaction can ameliorate RTH phenotypes.

Main Methods:

  • Crossed Thrb(PV) mice (RTH model) with Ncor1(ΔID) mice lacking TR/mutant TR binding.
  • Assessed thyroid-stimulating hormone (TSH), thyroid hormone (TH) levels, and RTH hallmarks in the resulting offspring.

Main Results:

  • The Ncor1(ΔID) mutation partially corrected elevated TSH and TH levels in Thrb(PV) mice.
  • Thyroid hyperplasia, weight loss, and other RTH symptoms were also partially reverted.
  • These findings support the hypothesis that aberrant NCOR1 recruitment by RTH TRβ mutants causes RTH.

Conclusions:

  • Aberrant NCOR1 recruitment by RTH TRβ mutants is a key mechanism driving RTH.
  • Targeting the TR-NCOR1 interaction presents a potential therapeutic strategy for RTH.

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