Project 171208

The tumor suppressor pRb is lost by mutations or functional inactivation in most, if not all, human cancers. The prevailing view is pRb controls cell proliferation and survival as well as differentiation (i.e. by stimulating the differentiation program). However, we have now demonstrated that during muscle differentiation in culture, pRb is not required for differentiation per se but only for allowing cells to withdraw from the cell cycle and survive during the transition from the proliferative to differentiative states. Specifically we showed that in the absence of pRb, differentiating myoblasts undergo autophagy (self eating) and that inhibition of autophagy allows myoblasts to differentiate and form twitching muscles in the absence of pRb. These results have important implications both to cancer therapy as they suggest that Rb deficient tumors can be induced to differentiate, and to muscular diseases, as autophagy plays an important role in muscle atrophy and several types of muscular dystrophies. We propose a series of experiments to delineate the exact mechanisms by which pRb inhibits autophagy in vitro and in vivo in both differentiating myoblasts and post-mitotic muscles and well as define the role of E2F1-3, the major targets of pRb, in the induction of autophagy in Rb deficient cells.

delineating the mechanisms by which the pRb tumor suppressor inhibits autophagy in muscle differentiation and cancer