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

Cell Cycle. 2011 May 15;10(10):1533-9. doi: 10.4161/cc.10.10.15520. Epub 2011 May 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cell Differentiation
  • Cell Hypoxia
  • Cells, Cultured
  • Cyclin D3 / metabolism
  • Lithium / pharmacology
  • Mice
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Retinoblastoma Protein / physiology
  • Tumor Suppressor Protein p53 / metabolism
  • beta Catenin / metabolism

Substances

  • Cyclin D3
  • Proto-Oncogene Proteins c-bcl-2
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Lithium