Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter.
Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter.
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DOI：
10.1016/j.bbrc.2013.09.061
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发表时间：
2013-10-11
影响因子：
3.1
通讯作者：
Ito, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Matsui, Keiji;Oda, Kasumi;Mizuta, Shumpei;Ishino, Ruri;Urahama, Norinaga;Hasegawa, Natsumi;Roeder, Robert G.;Ito, Mitsuhiro
MED1亚基的中介转录辅调节复合物是一种核受体特异性辅激活剂。促甲状腺激素（TSH，或促甲状腺激素）在三碘甲腺原氨酸（T3）存在下在促甲状腺细胞中表达的负反馈机制由TSHβ基因启动子上的配体甲状腺激素受体β（TRβ）采用，其中常规组蛋白修饰辅激活因子作为辅阻遏物。我们现在提供的证据表明，MED1是这个启动子上的配体依赖性正辅因子。在MED1突变小鼠中，TSHβ基因转录减弱，其中MED1的核受体结合能力被特异性破坏。在培养细胞中，MED1以配体非依赖性方式刺激GATA 2和Pit 1介导的TSHβ基因启动子活性。MED1还以T3依赖性方式刺激TSHβ基因启动子的转录。当T3依赖性辅阻遏物SRC1、SRC2和HDAC2下调时，转录进一步增强。因此，MED1是TSHβ基因启动子上的T3依赖性和非依赖性共激活因子。
The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor β (TRβ) on the TSHβ gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHβ gene promoter.
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