Sharma D, Fondell J D
Department of Physiology, University of Maryland School of Medicine, Baltimore 21201, USA.
Mol Endocrinol. 2000 Dec;14(12):2001-9. doi: 10.1210/mend.14.12.0567.
Thyroid hormone receptors (TRs) regulate transcription by recruiting distinct coregulatory complexes to target gene promoters. Coactivators implicated in ligand-dependent activation by TR include p300, the CREB-binding protein (CBP), members of the p160/SRC family, and the multisubunit TR-associated protein (TRAP) complex. Using a stable TR-expressing HeLa cell line, we show that interaction of TR with members of the p160/SRC family, CBP, and the p300/CBP-associated factor (PCAF) occurs rapidly (approximately 10 min) following addition of thyroid hormone (T3). In close agreement with these observations, we find that TR is associated with potent histone acetyltransferase activity rapidly following T3-treatment. By contrast, we observe that formation of TR-TRAP complexes occurs significantly later (approximately 3 h) post T3 treatment. An examination of the kinetics of T3-induced gene expression in HeLa cells reveals bimodal or delayed activation on specific T3-responsive promoters. Taken together, our data are consistent with the hypothesis that T3-dependent activation at specific target promoters may involve the regulated action of multiple TR-coactivator complexes.
甲状腺激素受体（TRs）通过招募不同的共调节复合物至靶基因启动子来调控转录。参与TR依赖配体激活的共激活因子包括p300、CREB结合蛋白（CBP）、p160/SRC家族成员以及多亚基TR相关蛋白（TRAP）复合物。利用稳定表达TR的HeLa细胞系，我们发现添加甲状腺激素（T3）后，TR与p160/SRC家族成员、CBP以及p300/CBP相关因子（PCAF）的相互作用迅速发生（约10分钟）。与这些观察结果密切一致的是，我们发现T3处理后，TR迅速与强大的组蛋白乙酰转移酶活性相关联。相比之下，我们观察到TR-TRAP复合物的形成在T3处理后显著延迟（约3小时）。对HeLa细胞中T3诱导基因表达动力学的研究揭示了在特定T3反应性启动子上的双峰或延迟激活。综上所述，我们的数据与以下假设一致：特定靶启动子上T3依赖的激活可能涉及多种TR-共激活因子复合物的调节作用。
