There is a significant void in our understanding of how individual members of the BCL2 family of proteins are regulated upstream of the mitochondria.  In this grant we will test our hypothesis that individual anti-apoptotic BCL2 proteins have unique biochemical properties and these unique properties not ony dictate their in vivo oncogenic potential, but also determine their importance in human malignancies.  We have previously performed unbiased approaches to begin to identify proteins that are capable of interacting with individual anti-apoptotic BCL2 proteins through non-BH domain mechanisms (BH = Bcl2 homology).  In this proposal we will build upon initial observations and perform three lines of experimentation that will advance our understnding of how non-canonical regulators of BCL2 family proteins are involved in human cancer.  First, we will extend the findings we previously reported and examine, in depth, the role of BCLb/BCL2L10 and its novel interacting protein Ubiquilin in lung adenocarcinoma.  Second, we will perform experiments to enhance and filter the data that we have generated from immunoprecipitation followed by mass spectrometry experiments, which will lead to the identification and characterization of additional BCL2-family interacting proteins.  Finally, we will determine how the differential response of BCL2-like proteins to proteasome inhibition alters patient response following treatment with clinically used proteasome inhibitors.  The culmination of these data will advance two critical aspects of our understanding of human cancer; first, we will increae our pool of potential therapeutic targets by identifying novel regulators of apoptosis, and, second, we will identify and characterize novel biomarkers that will predict therapeutic response in patients.