Weiss R E, Xu J, Ning G, Pohlenz J, O'Malley B W, Refetoff S
Department of Medicine,Jr Mental Retardation Research Center, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
EMBO J. 1999 Apr 1;18(7):1900-4. doi: 10.1093/emboj/18.7.1900.
Steroid receptor co-activator 1 (SRC-1) is a transcription co-factor that enhances the hormone-dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC-1 is necessary for the full expression of TH effect. SRC-1 knockout mice (SRC-1(-/-)) provide a model to examine the role of this co-activator on TH action in vivo. At baseline, SRC-1(-/-) mice display resistance to TH (RTH) as evidenced by a 2.5-fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild-type (SRC-1(+/+)) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC-1(+/+) and SRC-1(-/-) mice observed at baseline. In contrast, the decline of TSH by treatment with L-triiodothyronine was severely blunted in SRC-1(-/-) mice. These data indicate that SRC-1 is not required for the upregulation of TSH in TH deficiency. However, SRC-1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co-factor other than TR. It supports the hypothesis that a putative defect in the SRC-1 gene or another co-factor could be the cause of RTH in humans without mutations in the TR genes.
类固醇受体共激活因子1（SRC-1）是一种转录辅因子，可增强由甲状腺激素（TH）受体（TR）和其他核受体介导的激素依赖性作用。体外研究表明，SRC-1是TH效应充分表达所必需的。SRC-1基因敲除小鼠（SRC-1（-/-））为研究这种共激活因子在体内TH作用中的角色提供了一个模型。在基线时，SRC-1（-/-）小鼠表现出对TH的抵抗（RTH），血清TSH水平升高2.5倍即为证据，尽管与野生型（SRC-1（+/+））小鼠相比，血清游离TH水平增加了50%。当小鼠甲状腺功能减退时，TSH水平升高，消除了在基线时观察到的SRC-1（+/+）和SRC-1（-/-）小鼠之间的差异。相反，在SRC-1（-/-）小鼠中，用L-三碘甲状腺原氨酸治疗导致的TSH下降严重减弱。这些数据表明，在TH缺乏时，SRC-1不是TSH上调所必需的。然而，SRC-1增强了TH对TSH下调的敏感性。这是首次证明由TR以外的辅因子缺陷引起的RTH。它支持这样一种假说，即SRC-1基因或另一种辅因子中的假定缺陷可能是人类TR基因无突变情况下RTH的原因。
