Kamiya Yuji, Zhang Xiao-Yong, Ying Hao, Kato Yusuhito, Willingham Mark C, Xu Jianming, O'Malley Bert W, Cheng Sheue-Yann
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Endocrinology. 2003 Sep;144(9):4144-53. doi: 10.1210/en.2003-0239.
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.
甲状腺激素受体-β基因（TRβ）突变会导致甲状腺激素抵抗。突变型甲状腺激素核受体（TRs）在体内的作用是如何被调控的尚不清楚。我们通过使用甲状腺激素抵抗小鼠模型TRβPV基因敲入小鼠（处于SRC-1基因缺失背景下），研究了一种TR共激活因子——类固醇受体共激活因子-1（SRC-1）对靶组织反应性的影响。SRC-1的缺失加剧了垂体-甲状腺轴的功能障碍，并损害了TRβ（PV/+）小鼠的生长，但对TRβ（PV/PV）小鼠没有影响。然而，在TRβ（PV/PV）小鼠中，SRC-1的缺失加剧了甲状腺滤泡细胞向乳头状增生的病理进展，这类似于乳头状瘤形成。相比之下，SRC-1的缺失在TRβ（PV/+）或TRβ（PV/PV）小鼠中均未影响肝脏在调节血清胆固醇方面的反应性。SRC-1的缺失导致垂体和肝脏中几个T3靶基因的异常表达模式发生变化。因此，本研究表明，像SRC-1这样的共激活因子可以以组织依赖的方式调节TRβ突变体在体内的作用。
