MARC Predoctoral Fellowship Program

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DESCRIPTION (provided by applicant): The process of autophagy is a complex catabolic program for lysosomal degradation of proteins and other subcellular constituents. It is important for normal growth control and is defective in a number of cancers. Beclin 1 gene is the first mammalian gene identified involved in autophagy. Mono-allelic deletions of Beclin 1 gene are identified in 40 -75% of human sporadic breast, ovarian and prostate cancers. Homozygous Beclin 1 knockout mice are embryonic lethal, while the heterozygous Beclin 1 knockout mice develop various tumors. This mouse genetic result provides compelling evidence that autophagy plays an important role in preventing tumorigenesis. However, exactly why the Beclin 1 gene and autophagy are critical for tumor suppression remains unknown. The re-activation of autophagy may be an efficient cancer therapeutic strategy. Preliminary data indicates that exogenous expression of the Beclin 1 mutant which mimics constitutive phosphorylation in MCF7 cells results in the activation of autophagy. This tool will be used to construct cellular and animal models to characterize the consequence of re-activating autophagy.