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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Involvement of β-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells
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Involvement of β-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells

机译：β-catenin参与以及CBP和p300在雪旺细胞中糖皮质激素信号传导中的异常行为

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In the nervous system, glucocorticosteroid hormones play a major role during development and adult life. Myelin-forming cells are among the targets of glucocorticosteroids, which have been shown to promote myelination both in the central and peripheral nervous system. Glucocorticosteroid-stimulated gene transcription is mediated by the glucocorticosteroid receptor (GR) that recruits coac-tivators of the p160 family, forming a docking platform for secondary coactivators, such as cAMP-response element binding protein (CREB)-binding protein (CBP) or its close homologue, p300. Here, we investigated the role of CBP and p300 in mouse Schwann cells (MSC80). We show that, although the CBP/p300 binding domain of steroid receptor coactivator-1 is crucial for GR transac-tivation, neither CBP nor p300 enhanced GR transcriptional activation, as shown by overexpression and small interfering RNA (siRNA) knocking-down experiments. Unexpectedly, overexpression of p300, considered as a coactivator of the GR, resulted in inhibition of GR transcriptional activity. Studies with p300 deletion mutants demonstrated that p300-dependent repression is related to its acetyltransferase activity. Functional and pull-down assays showed that β-catenin may be the coactivator replacing CBP in the GR transcriptional complex. Our results suggest the formation of a GR-coactivator complex within Schwann cells, indicating that glucocorticosteroids may act by means of unusual partners in the nervous system, and we show a repressive effect of p300 on nuclear receptors.
机译：在神经系统中，糖皮质激素在发育和成年生活中起主要作用。形成髓磷脂的细胞是糖皮质激素的靶标之一，糖皮质激素已被证明可促进中枢和周围神经系统的髓鞘形成。糖皮质激素受体（GR）介导糖皮质激素类固醇刺激的基因转录，该受体募集p160家族的共激活因子，形成次级共激活因子的对接平台，例如cAMP反应元件结合蛋白（CREB）结合蛋白（CBP）或其紧密同源物，p300。在这里，我们研究了CBP和p300在小鼠雪旺细胞（MSC80）中的作用。我们显示，尽管类固醇受体共激活因子1的CBP / p300结合域对于GR的转运至关重要，但CBP和p300均未增强GR转录激活，如过表达和小的干扰RNA（siRNA）敲低实验所示。出乎意料的是，被认为是GR的共激活因子的p300的过度表达导致GR转录活性的抑制。对p300缺失突变体的研究表明，p300依赖性阻抑与其乙酰转移酶活性有关。功能和下拉分析表明，β-catenin可能是替代GR转录复合物中CBP的共激活因子。我们的结果表明，雪旺细胞中GR-coactivator复合物的形成，表明糖皮质激素可能通过神经系统中的异常伴侣起作用，并且我们显示了p300对核受体的抑制作用。

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