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Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone
Yuji Kamiya1, Xiao-Yong Zhang, Hao Ying
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Abstract:
Mutations in the thyroid hormone receptor-beta gene (TR beta) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TR beta PV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TR beta(PV/+) mice but not in TR beta(PV/PV) mice. In TR beta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TR beta(PV/+) or TR beta(PV/PV) mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T(3) target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner.
Insights
Steroid receptor coactivator-1 (SRC-1) modulates thyroid hormone receptor-beta (TR beta) mutant action. Its absence worsens pituitary-thyroid dysfunction and growth issues, but impacts thyroid cell changes differently based on TR beta mutation severity.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Mutations in the thyroid hormone receptor-beta (TR beta) gene lead to resistance to thyroid hormone (RTH).
- The in vivo regulation of mutant TRs' actions remains incompletely understood.
- Steroid receptor coactivator-1 (SRC-1) is a key coactivator for nuclear receptors.
Purpose of the Study:
- To investigate the role of SRC-1 in modulating the in vivo function of mutant TR beta.
- To assess the impact of SRC-1 deficiency on target tissue responsiveness in a mouse model of RTH.
Main Methods:
- Utilized a TR beta PV knockin mouse model crossed with SRC-1 null mice.
- Analyzed the pituitary-thyroid axis function, growth, liver cholesterol regulation, and gene expression patterns.
- Compared responses in mice with different TR beta genotypes (TR beta(PV/+) and TR beta(PV/PV)) and SRC-1 status (wild-type vs. null).
Main Results:
- SRC-1 deficiency exacerbated pituitary-thyroid axis dysfunction and impaired growth in TR beta(PV/+) mice.
- In TR beta(PV/PV) mice, SRC-1 absence intensified thyroid follicular cell hyperplasia but did not affect liver cholesterol regulation.
- SRC-1 deficiency altered the expression of several thyroid hormone target genes in the pituitary and liver.
Conclusions:
- SRC-1 plays a critical role in modulating the in vivo action of mutant TR beta.
- The effect of SRC-1 is tissue-dependent, influencing pituitary-thyroid function and thyroid cell pathology differently.
- Coactivator availability can significantly impact the phenotypic severity of resistance to thyroid hormone.