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结节性硬化症蛋白通过与 p62 和泛素结合,激活并控制 Rac1 的分布,这一过程通过 mTORC1 信号通路来实现。

Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway.

机构信息

Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.

出版信息

Int J Oncol. 2013 Aug;43(2):447-56. doi: 10.3892/ijo.2013.1984. Epub 2013 Jun 12.

Abstract

Recent studies indicated that the tuberous sclerosis 2 (TSC2) gene product, tuberin, regulates Rac1 activity. However, the underlying mechanism by which tuberin regulates Rac1 activity has not been clearly elucidated to date. To better understand the molecular link between tuberin function and Rac1, we characterized the activity and distribution of Rac1 in mouse Tsc2-deficient renal tumor cells using restoration experiments with wild-type tuberin. Rac1 activity was significantly higher in tuberin-expressing cells compared with control Tsc2-deficient cells. Further, Rac1 activation was induced by rapamycin treatment or knockdown of raptor, but not rictor, in Tsc2-deficient cells, indicating that mTORC1 is an upstream negative regulator of Rac1. Intriguingly, Rac1 appeared to form cytoplasmic dots in Tsc2-deficient cells, but not in tuberin-expressing and since rapamycin treatment dispersed these dots, involvement of aberrant mTOR complex 1 (mTORC1) activation in the dot formation was suspected. Moreover, the dots were co-localized with p62/sequestosome-1 and ubiquitin. These findings imply that Rac1 distribution and/or its degradation may be regulated by tuberin through the mTORC1 signaling pathway.

摘要

最近的研究表明,结节性硬化症 2 (TSC2) 基因产物,结节蛋白,调节 Rac1 活性。然而,到目前为止,结节蛋白调节 Rac1 活性的潜在机制尚未被清楚阐明。为了更好地理解结节蛋白功能与 Rac1 之间的分子联系,我们使用野生型结节蛋白进行恢复实验,对小鼠 Tsc2 缺陷型肾肿瘤细胞中的 Rac1 活性和分布进行了表征。与对照 Tsc2 缺陷细胞相比,表达结节蛋白的细胞中 Rac1 活性明显更高。此外,雷帕霉素处理或 Raptor 敲低可诱导 Tsc2 缺陷细胞中的 Rac1 激活,但 Rictor 敲低则不能,这表明 mTORC1 是 Rac1 的上游负调控因子。有趣的是,Rac1 在 Tsc2 缺陷细胞中似乎形成细胞质斑点,但在表达结节蛋白的细胞中则没有,由于雷帕霉素处理可分散这些斑点,因此怀疑异常 mTOR 复合物 1 (mTORC1) 的激活参与了斑点的形成。此外,这些斑点与 p62/自噬体 1 和泛素共定位。这些发现表明,Rac1 的分布和/或其降解可能通过 mTORC1 信号通路被结节蛋白调节。

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