期刊
ENDOCRINOLOGY
卷 144, 期 9, 页码 4144-4153出版社
ENDOCRINE SOC
DOI: 10.1210/en.2003-0239
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资金
- NICHD NIH HHS [HD07857] Funding Source: Medline
Mutations in the thyroid hormone receptor-beta gene (TRbeta) 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, TRbetaPV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TRbeta(PV/+) mice but not in TRbeta(PV/PV) mice. In TRbeta(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 TRbeta(PV/+) or TRbeta(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 TRbeta mutants in a tissue-dependent manner.
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