Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.
Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.
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DOI：
10.18632/oncotarget.7581
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Baek KH
中科院分区：
文献类型：
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作者：
Lim KH;Suresh B;Park JH;Kim YS;Ramakrishna S;Baek KH
致命巨型幼虫（Lgl）基因编码皮层细胞骨架蛋白Lgl，并参与维持细胞极性和上皮完整性。先前，我们观察到果蝇肿瘤抑制蛋白Lgl的哺乳动物同源物Mgl-1通过泛素-蛋白酶体途径被降解，而支架蛋白RanBPM阻止了Mgl-1蛋白的周转。因此，RanBPM的过表达增强了mgl -1介导的细胞增殖和迁移。在这里，我们分析了泛素特异性蛋白酶11 （USP11）作为Mgl-1的新调节剂的能力，它需要RanBPM来调节蛋白酶体对Mgl-1的降解。USP11具有去泛素化活性，稳定了mg -1蛋白。然而，usp11介导的Mgl-1稳定在ranbpm敲低的细胞中被抑制。此外，在癌细胞迁移过程中，USP11对Mgl-1的调控需要RanBPM的表达。此外，一项体内研究表明，USP11的缺失会导致肿瘤的形成。综上所述，研究结果表明USP11通过RanBPM调控Mgl-1蛋白降解而发挥抑癌作用。
The Lethal giant larvae (Lgl) gene encodes a cortical cytoskeleton protein, Lgl, and is involved in maintaining cell polarity and epithelial integrity. Previously, we observed that Mgl-1, a mammalian homologue of the Drosophila tumor suppressor protein Lgl, is subjected to degradation via ubiquitin-proteasome pathway, and scaffolding protein RanBPM prevents the turnover of the Mgl-1 protein. Consequently, overexpression of RanBPM enhances Mgl-1-mediated cell proliferation and migration. Here, we analyzed the ability of ubiquitin-specific protease 11 (USP11) as a novel regulator of Mgl-1 and it requires RanBPM to regulate proteasomal degradation of Mgl-1. USP11 showed deubiquitinating activity and stabilized Mgl-1 protein. However, USP11-mediated Mgl-1 stabilization was inhibited in RanBPM-knockdown cells. Furthermore, in the cancer cell migration, the regulation of Mgl-1 by USP11 required RanBPM expression. In addition, an in vivo study revealed that depletion of USP11 leads to tumor formation. Taken together, the results indicated that USP11 functions as a tumor suppressor through the regulation of Mgl-1 protein degradation via RanBPM.