Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone

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.