E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode
E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode
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DOI：
10.1073/pnas.0501491102
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发表时间：
2005-05-03
影响因子：
11.1
通讯作者：
Walfish, PG
中科院分区：
文献类型：
--
作者：
Meng, XW;Webb, P;Walfish, PG
未配体的甲状腺激素（TH）受体（TR）和其他核受体（NR）通过募集辅阻遏物（CoR），如NR CoR（N-CoR）和SMRT，抑制转录激活基因的转录。未配体的TR也激活TH抑制基因的转录。一些证据表明，这些影响也涉及TR/CoR接触;然而，在这些情况下，CoR激活转录的确切原因尚不清楚。解开这些机制是复杂的事实，这是很难破译的直接与间接的影响，在哺乳动物细胞中的TIR-辅调节接触。在这项研究中，我们使用酵母，酿酒酵母，缺乏内源性NR和NR辅助调节，以确定如何unliganded TR可以激活转录。我们以前表明，腺病毒5早期区域1A共激活未配体的TRs在酵母中，这些影响被TH阻断。我们在这里显示，人腺病毒5型早期区域1A（E1 A）包含一个短肽（LDQLIEEVL氨基酸20-28），类似于CoR-NR相互作用基序（CoRNR盒），并且该基序是TR结合和共激活所需的。尽管全长N-CoR在酵母中不共激活TR，但天然存在的N-CoR变体（N-CoRl）和保留CoRNR盒但缺乏N-末端阻遏物结构域的人工N-CoR截短物（N-CoRc）表现为未配体TR的有效和直接TH-阻遏的共激活剂。我们的结论是，E1 A和N-CoR 1是天然存在的TR共激活剂，结合在典型的CoR模式，并建议类似的因素可以介导转录激活的unliganded TRs在哺乳动物中。
Unliganded thyroid hormone (TH) receptors (TRs) and other nuclear receptors (NRs) repress transcription of hormone-activated genes by recruiting corepressors (CoRs), such as NR CoR (N-CoR) and SMRT. Unliganded TRs also activate transcription of TH-repressed genes. Some evidence suggests that these effects also involve TR/CoR contacts; however, the precise reasons that CoRs activate transcription in these contexts are obscure. Unraveling these mechanisms is complicated by the fact that it is difficult to decipher direct vs. indirect effects of TIR-coregulator contacts in mammalian cells. In this study, we used yeast, Saccharomyces cerevisiae, which lack endogenous NRs and NR coregulators, to determine how unliganded TRs can activate transcription. We previously showed that adenovirus 5 early-region 1A coactivates unliganded TRs in yeast, and that these effects are blocked by TH. We show here that human adenovirus type 5 early region 1A (E1A) contains a short peptide (LDQLIEEVL amino acids 20-28) that resembles CoR-NR interaction motifs (CoRNR boxes), and that this motif is required for TR binding and coactivation. Although full-length N-CoR does not coactivate TR in yeast, a naturally occurring N-CoR variant (N-CoRl)) and an artificial N-CoR truncation (N-CoRc) that retain CoRNR boxes but lack N-terminal repressor domains behave as potent and direct TH-repressed coactivators for unliganded TRs. We conclude that E1A and N-CoRl are naturally occurring TR coactivators that bind in the typical CoR mode and suggest that similar factors could mediate transcriptional activation by unliganded TRs in mammals.