Jinesh Goodwin G, Kamat Ashish M
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Death Discov. 2017 May 29;3:17023. doi: 10.1038/cddiscovery.2017.23. eCollection 2017.
Cancer stem cells evade apoptotic death by blebbishield emergency program, which constructs blebbishields from apoptotic bodies and drives cellular transformation. Von Hippel-Lindau (VHL) plays both tumor suppressor and oncogenic roles, and the reason behind is poorly understood. Here we demonstrate that dimers and trimers of p19-VHL interact with RalBP1 to construct blebbishields. Expression of RalBP1, p19-VHL, and high-molecular weight VHL is required to evade apoptosis by blebbishield-mediated transformation. In contrast, p30-VHL plays a tumor suppressor role by inhibiting blebbishield-mediated transformation. Furthermore, target genes of VHL that suppress oxidative stress were elevated during blebbishield-mediated cellular transformation. Thus, RalBP1 and p19-VHL play an oncogenic role, whereas p30-VHL plays a tumor suppressor role during the blebbishield emergency program by regulating oxidative stress management genes.
癌症干细胞通过气泡护盾应急程序逃避凋亡死亡，该程序从凋亡小体构建气泡护盾并驱动细胞转化。冯·希佩尔-林道（VHL）蛋白兼具肿瘤抑制和致癌作用，其背后的原因尚不清楚。在此，我们证明p19-VHL的二聚体和三聚体与RalBP1相互作用以构建气泡护盾。RalBP1、p19-VHL和高分子量VHL的表达是通过气泡护盾介导的转化逃避凋亡所必需的。相比之下，p30-VHL通过抑制气泡护盾介导的转化发挥肿瘤抑制作用。此外，在气泡护盾介导的细胞转化过程中，VHL抑制氧化应激的靶基因表达升高。因此，RalBP1和p19-VHL发挥致癌作用，而p30-VHL在气泡护盾应急程序中通过调节氧化应激管理基因发挥肿瘤抑制作用。
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