The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression
The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression
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DOI：
10.1128/mcb.20.1.187-195.2000
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发表时间：
2000-01-01
影响因子：
5.3
通讯作者：
Moore, DD
中科院分区：
文献类型：
--
作者：
Lee, YK;Dell, H;Moore, DD
孤儿核激素受体SHP与许多其他核激素受体相互作用并抑制其转录活性。已经提出了几种机制来解释这种抑制。在这里，我们表明，SHP抑制反式激活孤儿受体肝细胞核因子4（HNF-4）和类维生素A X受体（RXR）至少有两种机制。SHP与转录辅激活因子识别的相同HNF-4表面相互作用，并与它们竞争体内结合。以前发现的最小SHP序列需要与其他受体的相互作用是足以与HNF-4的相互作用，虽然删除结果表明，额外的C-末端序列是必要的充分结合和辅激活剂竞争。这些额外的序列包括与SHP的直接转录阻遏物活性相关的序列。SHP还与辅激活因子竞争结合配体激活的RXR，并且基于与其他核受体的配体依赖性相互作用，辅激活因子竞争可能是SHP介导的抑制的一般特征。如前所述，SHP的最小受体相互作用结构域足以与RXR完全相互作用。该结构域也足以进行充分的共激活剂竞争。然而，在功能上，RXR反式激活的完全抑制需要C-末端阻遏物结构域的存在，仅弱抑制与该受体相互作用结构域相关。总体而言，这些结果表明，SHP抑制核激素受体介导的反式激活通过两个独立的步骤：首先通过与辅激活因子的竞争，然后通过其转录抑制因子功能的直接影响。
The orphan nuclear hormone receptor SHP interacts with a number of other nuclear hormone receptors and inhibits their transcriptional activity. Several mechanisms have been suggested to account for this inhibition. Here we show that SHP inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (HNF-4) and the retinoid X receptor (RXR) by at least two mechanisms. SHP interacts with the same HNF-4 surface recognized by transcriptional coactivators and competes with them for binding in vivo. The minimal SHP sequences previously found to be required for interaction with other receptors are sufficient for interaction with HNF-4, although deletion results indicate that additional C-terminal sequences are necessary for full binding and coactivator competition. These additional sequences include those associated with direct transcriptional repressor activity of SHP. SHP also competes with coactivators for binding to ligand-activated RXR, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of SHP-mediated repression. The minimal receptor interaction domain of SHP is sufficient for full interaction with RXR, as previously described. This domain is also sufficient for full coactivator competition. Functionally, however, full inhibition of RXR transactivation requires the presence of the C-terminal repressor domain, with only weak inhibition associated with this receptor interaction domain. Overall, these results suggest that SHP represses nuclear hormone receptor-mediated transactivation via two separate steps: first by competition with coactivators and then by direct effects of its transcriptional repressor function.