An important regulator of autophagy in mammals and yeast is beclin 1/Atg6/Vps30. Yeast Atg6/Vps30p was identified in genetic screens for mutants that are starvation-sensitive, or defective in vacuolar protein sorting. Human Beclin1 was originally identified as a protein interacting with the anti-apoptotic protein Bcl-2 in a yeast two-hybrid assay. In both, yeast and mammalian cells, Atg6/Vps30/Beclin 1 complexes with Class III phosphatidylinositol 3-kinase (PI3K) and is required for autophagosome formation. Whereas the interaction of Beclin 1 and Bcl-2 has been recently characterized little is known about the genes that are downstream of beclin 1. We have established C. elegans as a multicellular genetic model system to study autophagy in vivo. We have shown that
bec-1 mediated autophagy has functions in various fundamental biological processes, including survival, fat storage, longevity, dauer and reproductive development. In addition, we have shown that
bec-1 dependent autophagy is negatively regulated by the oncogenic phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, and positively regulated by the PTEN tumor suppressor gene. These results resonate with the analysis in vertebrates where beclin 1 acts as a tumor supressor gene. The focus of our project is the elucidation of the regulatory mechanisms of autophagy in C. elegans, through the identification of genes that interact with
bec-1 (
bec-1 is the ortholog of Atg6/Vps30/Beclin 1). We have obtained a complete loss of function mutant in C. elegans
bec-1 which has been shown to be essential for viability. We have isolated mutants that suppress the
bec-1 dependent lethality and named these mutants sub mutants (suppressor of
bec-1 induced lethality). We hypothesize that these suppressor mutations of the
bec-1 lethal phenotype may identify new proteins that interact with BEC-1, and since autophagy has been linked to tumor suppression, molecular characterization of any
bec-1 interacting gene may identify a new candidate gene involved in cancer biology. We will report on the molecular and genetic characterization of these suppressor mutations.