Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
Cell Cycle. 2011 May 15;10(10):1533-9. doi: 10.4161/cc.10.10.15520.
Inactivation of the tumor suppressor RB1 leads to cell proliferation, cell death and abortive differentiation in certain tissues and physiological contexts. Anti-apoptotic signals are thought to be the most important mechanism by which RB1-mutant cells escape cell death. Indeed, in the course of neoplastic transformation RB1 is often inactivated in conjunction with a mutation in the pro-apoptotic tumor suppressor p53. We have previously devised a biological framework to identify factors that maintain survival of differentiating Rb-deficient muscle fibers. We showed that differentiating Rb-deficient myoblasts fuse to form short myotubes that degenerate in a process associated with enhanced autophagy, and that degeneration was rescued by antagonists of apoptosis or autophagy, induction of mitochondrial-biogenesis or hypoxia-induced glycolytic shift, leading to long, twitching myotubes. Here, we also show that lithium slows the collapse of Rb-deficient myotubes and surprisingly, this is independent of autophagy, cyclin D3 and β-catenin. Thus, several distinct processes can suppress cell death induced by RB1 loss. We discuss these pathways and how they may cooperate with RB1 inactivation in the course of cancer initiation.
肿瘤抑制因子 RB1 的失活会导致某些组织和生理环境中的细胞增殖、细胞死亡和未分化分化。抗细胞凋亡信号被认为是 RB1 突变细胞逃避细胞死亡的最重要机制。事实上，在肿瘤转化过程中，RB1 经常与促凋亡肿瘤抑制因子 p53 的突变同时失活。我们之前设计了一个生物框架来识别维持分化的 Rb 缺陷肌纤维存活的因素。我们表明，分化的 Rb 缺陷成肌细胞融合形成短肌管，在与增强自噬相关的过程中退化，凋亡或自噬的拮抗剂、诱导线粒体生物发生或缺氧诱导的糖酵解转移可以挽救退化，导致长而抽搐的肌管。在这里，我们还表明锂可以减缓 Rb 缺陷肌管的崩溃，令人惊讶的是，这与自噬、细胞周期蛋白 D3 和 β-连环蛋白无关。因此，几种不同的过程可以抑制由 RB1 缺失引起的细胞死亡。我们讨论了这些途径，以及它们如何在癌症发生过程中与 RB1 失活协同作用。
