Importance of steroid receptor coactivators in the modulation of steroid action on brain and behavior.
Importance of steroid receptor coactivators in the modulation of steroid action on brain and behavior.
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DOI：
10.1016/j.psyneuen.2009.05.004
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发表时间：
2009-12-01
影响因子：
3.7
通讯作者：
Charlier, Thierry D
中科院分区：
文献类型：
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作者：
Charlier, Thierry D
类固醇受体如雌激素和雄激素受体是参与大量靶基因转录调控的核受体。脑中的类固醇依赖性蛋白质表达控制着大量的生物学过程，包括空间认知、交配行为和神经保护。两种不同核受体之间竞争或压制的发现引入了共同辅因子可能参与调节核受体转录活性的概念。这些辅因子或辅调节蛋白在功能上分为辅激活子和辅抑制子，并参与染色质重塑和一般转录机制的稳定。虽然已经收集了大量的信息，在体外功能的这些辅助调节蛋白，相对较少的是已知的关于它们在体内的生理作用，特别是在大脑中。本实验室和其他实验室已经证明SRC-1在类固醇依赖性行为的分化和激活以及相关神经基因中的重要性。例如，我们报道SRC-1表达的抑制阻断了外源性睾酮对男性性行为的激活作用，并增加了正中视前区的体积。其他辅激活因子可能参与类固醇受体活性的体内调节，并且似乎辅激活因子的精确子集的存在可以通过在类固醇受体活化后调节特定的下游途径来帮助定义细胞的表型。非常大量的共激活因子和它们与预先形成的复合物的结合可能允许确定数百种不同的表型。需要研究共激活因子的表达及其在体内的功能，以充分了解类固醇在脑中的作用和特异性。
Steroid receptors such as estrogen and androgen receptors are nuclear receptors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent protein expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelching, between two different nuclear receptors introduced the notion that common cofactors may be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors or coregulatory proteins are functionally divided into coactivators and corepressors and are involved in chromatin remodeling and stabilization of the general transcription machinery. Although a large amount of information has been collected about the in vitro function of these coregulatory proteins, relatively little is known regarding their physiological role in vivo, particularly in the brain. Our laboratory and others have demonstrated the importance of SRC-1 in the differentiation and activation of steroid-dependent sexual behaviors and the related neural genes. For example, we report that the inhibition of SRC-1 expression blocks the activating effects of exogenous testosterone on male sexual behaviors and increases the volume of the median preoptic area. Other coactivators are likely to be involved in the modulation in vivo of steroid receptor activity and it seems that the presence of a precise subset of coactivators could help define the phenotype of the cell by modulating a specific downstream pathway after steroid receptor activation. The very large number of coactivators and their association into preformed complexes potentially allows the determination of hundreds of different phenotypes. The study of the expression of the coactivator and their function in vivo is required to fully understand steroid action and specificity in the brain.