RalBP1 and p19-VHL play an oncogenic role, and p30-VHL plays a tumor suppressor role during the blebbishield emergency program.

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.