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首页> 外文期刊>Molecular and Cellular Biology >Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4α1: Modulation by the F Domain
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Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4α1: Modulation by the F Domain

机译：孤儿受体肝细胞核因子4α1竞争性辅因子的招募：F域的调制。

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For most ligand-dependent nuclear receptors, the status of endogenous ligand modulates the relative affinities for corepressor and coactivator complexes. It is less clear what parameters modulate the switch between corepressor and coactivator for the orphan receptors. Our previous work demonstrated that hepatocyte nuclear factor 4α1 (HNF4α1, NR2A1) interacts with the p160 coactivator GRIP1 and the cointegrators CBP and p300 in the absence of exogenously added ligand and that removal of the F domain enhances these interactions. Here, we utilized transient-transfection analysis to demonstrate repression of HNF4α1 activity by the corepressor silencing mediator of retinoid and thyroid receptors (SMRT) in several cell lines and on several HNF4α-responsive promoter elements. Glutathione S-transferase pulldown assays confirmed a direct interaction between HNF4α1 and receptor interaction domain 2 of SMRT. Loss of the F domain resulted in marked reduction of the ability of SMRT to interact with HNF4α1 in vitro and repress HNF4α1 activity in vivo, although the isolated F domain itself failed to interact with SMRT. Surprisingly, loss of both the A/B and F domains restored full repression by SMRT, suggesting involvement of both domains in the SMRT interaction. Finally, we show that when coexpressed along with HNF4α1 and GRIP1, CBP, or p300, SMRT can titer out HNF4α1-mediated transactivation in a dose-dependent manner and that this competition derives from mutually exclusive binding. Collectively, these results suggest that HNF4α can functionally interact with both a coactivator and a corepressor without altering the status of any putative ligand and that the presence of the F domain may play a role in discriminating between the different coregulators.
机译：对于大多数依赖配体的核受体，内源性配体的状态调节了对于corepressor和coactivator复合物的相对亲和力。尚不清楚什么参数调节孤儿受体的共加压因子和共活化因子之间的转换。我们以前的工作表明，在不存在外源添加配体的情况下，肝细胞核因子4α1（HNF4α1，NR2A1）与p160辅助激活剂GRIP1和协整剂CBP和p300相互作用，并且去除F结构域会增强这些相互作用。在这里，我们利用瞬时转染分析来证明在几种细胞系中以及在几种HNF4α响应性启动子元件上，类视色素和甲状腺受体（SMRT）的核心加压因子沉默介导物对HNF4α1活性的抑制作用。谷胱甘肽 S -转移酶下拉实验证实HNF4α1与SMRT受体相互作用域2之间存在直接相互作用。尽管分离的F结构域本身不能与SMRT相互作用，但是F结构域的丧失导致SMRT在体外与HNF4α1相互作用并在体内抑制HNF4α1活性的能力显着降低。出人意料的是，A / B和F结构域的缺失恢复了SMRT的完全抑制，表明这两个结构域都参与了SMRT相互作用。最后，我们显示，当与HNF4α1和GRIP1，CBP或p300共表达时，SMRT可以剂量依赖的方式滴定HNF4α1介导的反式激活，这种竞争源自相互排斥的结合。总的来说，这些结果表明，HNF4α可以在不改变任何假定配体状态的情况下与共激活因子和共抑制因子功能相互作用，并且F结构域的存在可能在区分不同的共调控因子中发挥作用。

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