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Autophagy is frequently observed in dying cells. However, it has been unclear whether autophagy is a form of non-apoptotic programmed cell death, whether it is activated as part of a cellular survival strategy, or whether it is activated to clean up the remnants of dying cells. With the identification of the evolutionarily conserved molecular machinery, it has become possible to use genetic approaches to resolve this controversy. The preponderance of genetic evidence to date indicates that autophagy is primarily a pro-survival mechanism, but in certain contexts, can also be a mechanism of cell death. We have found that the interaction between the anti-apoptotic protein, Bcl-2, and the autophagy protein, Beclin 1, functions as a rheostat that controls levels of cellular autophagy and autophagic cell death. Current studies are aimed at: (1) identifying the mechanisms by which Bcl-2 inhibits the autophagy function of Beclin 1; (2) identifying the upstream signaling events that regulate Bcl-2-Beclin 1 binding; (3) evaluating the role of Bcl-2 inhibition of autophagy in oncogenesis; (4) evaluating the role of Bcl-2 and Beclin 1 binding in cell death regulation during embryonic development; (5) evaluating the role of the interaction of the C. elegans orthologs of Bcl-2 and Beclin 1, CED-9 and BEC-1, in programmed cell death and development; (6) performing crystallographic analyses of the Bcl-2/Beclin 1 and CED-9/BEC-1 complexes; and (7) evaluating the role of autophagy in the clearance of dead cells during embryonic development. (View image) |
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