Journal
CELL CYCLE
Volume 10, Issue 10, Pages 1533-1539Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.10.15520
Keywords
survival pathways; pRb; p107; p130; skeletal myogenesis; muscle degeneration; Bcl-2; autophagy; mitochondria; hypoxia; cancer; lithium; cyclin D3
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Funding
- Canadian Institute of Health Research [MOP-93674]
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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 proapoptotic 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 beta-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.
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