Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: Evidence for haploinsufficiency
Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: Evidence for haploinsufficiency
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DOI：
10.1210/en.143.4.1554
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发表时间：
2002-04-01
期刊：
影响因子：
4.8
通讯作者：
Refetoff, S
中科院分区：
文献类型：
--
作者：
Weiss, RE;Gehin, M;Refetoff, S
类固醇受体辅助激活因子(SRC)-1和转录中介因子(TIF)-2是同源的核受体辅助激活因子。我们通过测量化合物SRC-1和TIF-2基因敲除(KO)小鼠的甲状腺功能，研究了它们作为甲状腺激素(TH)辅助激活因子的可能冗余。虽然SRC-1 KO(SRC-1(-/-))小鼠对TH具有抵抗力，但SRC-1(+/-)小鼠对TH没有抵抗力，我们现在证明TIF-2 KO(TIF-2(-/-))小鼠具有正常的甲状腺功能。然而，双杂合的SRC-1(+/-)/TIF-2(+/-)小鼠表现出与完全缺乏SRC-1的小鼠相似的对TH的抗性。SRC-1和TIF-2的KO均导致血清TH和促甲状腺激素浓度显著升高。这项工作证明了核共激活子中的基因剂量效应，表现为SRC-1和TIF-2的单倍体不足和功能冗余。
Steroid receptor coactivator (SRC) -1 and transcriptional intermediary factor (TIF) -2 are homologous nuclear receptor coactivators. We have investigated their possible redundancy as thyroid hormone (TH) coactivators by measuring thyroid function in compound SRC-1 and TIF-2 knock out (KO) mice. Whereas SRC-1 KO (SRC-1(-/-)) mice are resistant to TH and SRC-1(+/-) are not, we now demonstrate that TIF-2 KO (TIF-2(-/-)) mice have normal thyroid function. Yet double heterozygous, SRC-1(+/-)/TIF-2(+/-) mice manifested resistance to TH of a similar degree as that in mice completely deficient in SRC-1. KO of both SRC-1 and TIF-2 resulted in marked increases of serum TH and thyrotropin concentrations. This work demonstrates gene dosage effect in nuclear coactivators manifesting as haploinsufficiency and functional redundancy of SRC-1 and TIF-2.