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Sterol regulatory element binding protein-2 (SREBP-2) is a membrane bound transcription factor that upon proteolytic processing can activate the expression of genes involved in cholesterol biosynthesis and uptake. It has previously been shown that caspase-3 can cleave SREBP-2, independent of sterol regulation. Furthermore, we and others have demonstrated that the accumulation of misfolded proteins within the ER, a condition known as ER stress, can activate caspase-3 as well as dysregulate lipid metabolism by activating SREBPs. The purpose of this study is to determine if the mechanisms by which ER stress induces SREBP activity involves the activation of caspase-3. We hypothesize that the proteolytic processing of SREBP-2 by caspases may account for the uncontrolled production and uptake of lipids within the atherosclerotic plaque. A human breast adenocarcinoma cell line deficient in caspase-3 (MCF7) is used to evaluate the role of caspase-3 activation during ER stress. Wild type MCF7 and MCF7 cells stably transfected with the gene encoding caspase-3 (MCF7/cas3), were treated with the ER stress inducing agent, tunicamycin, to determine the effect of caspase-3 on SREBP-2 cleavage under ER stress conditions. Interestingly, under ER stress conditions induced by 24 hour treatment with 5 and 10 mg/ml tunicamycin, only MCF7/cas3 cells exhibit proteolytic cleavage of SREBP-2 to the characteristic 68 kDa size. This may imply that during ER stress, caspase-3 is selectively activated which leads to subsequent SREBP-2 processing. Wild type MCF7 and MCF7/cas3 cells were treated with the pro-apoptotic agent staurosporine, to activate all caspases. Preliminary results show that treatment with 1mM staurosporine for 4 hours increases SREBP-2 processing in both MCF7 and MCF7/cas3 cells. This result demonstrates that other caspases may play a role in releasing SREBP-2 from the ER membrane. The ability of ER stress to activate SREBP-2 through the induction of caspase-3 may contribute to foam cell formation and the emergence of a lipid rich necrotic core that is characteristic of advanced atherosclerotic lesions.