Cytosporone B is an agonist for nuclear orphan receptor Nur77
Cytosporone B is an agonist for nuclear orphan receptor Nur77
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Cytosporone B 是核孤儿受体 Nur77 的激动剂
DOI：
10.1038/nchembio.106
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发表时间：
2008-09-01
影响因子：
14.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
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作者：
Zhan, Yanyan;Du, Xiping;Wu, Qiao
核孤儿受体Nur77在许多生物学过程中发挥着重要作用。然而，Nur77的生理配体还没有确定。在这里，我们报告了八肽胞孢子酮B(CSN-B)是一种天然存在的Nur77激动剂。CSN-B特异性地与Nur77的配体结合域结合，并刺激Nur77依赖的靶基因的反式激活活性，包括Nr4a1(Nur77)本身，它包含多个共识反应元件，允许以CSN-B依赖的方式进行正向自动调节。CSN-B还可以提高空腹C57小鼠的血糖水平，这种效果伴随着多个参与糖异生的基因的诱导。在Nur77缺失(Nr4a1(-/-))小鼠中没有观察到这些生物学效应，这表明CSN-B通过Nur77调节糖异生。此外，CSN-B通过诱导Nur77的表达，将Nur77移位到线粒体，导致细胞色素c的释放，从而诱导细胞凋亡，抑制移植瘤的生长。因此，CSN-B可能是一种很有前途的治疗癌症和低血糖的药物，它也可能作为一种试剂来增加对Nur77生物学功能的了解。
Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1(-/-)) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.