Multiple pathways counteract cell death induced by RB1 loss: implications for cancer.

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.