Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms
Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms
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DOI：
10.1074/jbc.m106140200
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发表时间：
2002-01-18
影响因子：
4.8
通讯作者：
Choi, HS
中科院分区：
文献类型：
--
作者：
Sanyal, S;Kim, JY;Choi, HS
孤儿核受体小异源二聚体伴侣（SHP; NROB 2）与广泛的核受体相互作用，并抑制其转录活性。SHP表达受核受体超家族的几个其他成员调节，包括孤儿受体SF-1和LRH-1以及胆汁酸受体FXR。我们发现SHP启动子也被雌激素受体相关受体γ（ERR γ）激活，但不被相关的ERR α和ERR β亚型激活。SHP和ERR γ mRNA在几种组织中共表达，包括胰腺、肾脏和心脏，证实了这种反式激活的潜在相关性。ERR γ反式激活依赖于SF-1的五个先前表征的DNA结合位点中的仅一个，并且该元件不同于先前报道的ERR响应元件。然而，用组蛋白去乙酰化酶抑制剂利司他汀A治疗显著增加了该元件上的ERR α和ERR β活性，这表明ERR α和-β活性的缺乏可能取决于它们与体内辅阻遏物的关联。此外，使用DNA结合受体上的蛋白酶敏感性测定，证明了不同响应元件的DNA序列可以引起ERR蛋白的变构调节，这反过来可能是这些受体对不同响应元件的差异活性的原因。SHP抑制ERR γ反式激活，并与ERR亚家族的所有三个成员发生物理相互作用，如酵母双杂交和生化测定所示。与其他SHP靶点一样，这种相互作用依赖于ERR γ的AF-2辅激活剂结合位点和先前描述的SHP的N-末端受体相互作用结构域。最近描述的几种与人类中度肥胖相关的SHP突变阻断了ERR γ活性的抑制。总的来说，这些结果确定了一个新的自动调节环控制SHP基因的表达，并显着扩展了潜在的功能作用的三个ERRs。
The orphan nuclear receptor small heterodimer partner (SHP; NROB2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHP promoter is also activated by the estrogen receptor-related receptor gamma (ERRgamma) but not the related ERRalpha and ERRbeta isoforms. SHP and ERRgamma mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRgamma transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRalpha and ERRbeta activity on this element indicating that the lack of activity of ERRalpha and -beta may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRgamma transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRgamma and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRgamma activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs.