critical role of the rb family in myoblast survival and fusionrb家族的重要作用在成肌细胞生存和融合.pdf

Critical Role of the Rb Family in Myoblast Survival and Fusion 1 1¤ 2 1,3 Giovanni Ciavarra , Andrew T. Ho , David Cobrinik , Eldad Zacksenhaus * 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, 2 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, 3 Division of Cell and Molecular Biology, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada Abstract The tumor suppressor Rb is thought to control cell proliferation, survival and differentiation. We recently showed that differentiating Rb-deficient mouse myoblasts can fuse to form short myotubes that quickly collapse through a mechanism involving autophagy, and that autophagy inhibitors or hypoxia could rescue the defect leading to long, twitching myotubes. Here we determined the contribution of pRb relatives, p107 and p130, to this process. We show that chronic or acute inactivation of Rb plus p107 or p130 increased myoblast cell death and reduced myotube formation relative to Rb loss alone. Treatment with autophagy antagonists or hypoxia extended survival of double-knockout myotubes, which appeared indistinguishable from control fibers. In contrast, triple mutations in Rb, p107 and p130, led to substantial increase in myoblast death and to elongated bi-nuclear myocytes, which seem to derive from nuclear duplication, as opposed to cell fusion. Under hypoxia, some rare, abnormally thin triple knockout myotubes survived and twitched. Thus, mutation of p107 or p130 reduces survival of Rb-deficient myoblasts during differentiation but does