Control of caspase activation in apoptosis

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DESCRIPTION (provided by applicant): Inhibition of apoptosis is one of the hallmarks of cancer, which, together with increased cellular proliferation, leads to tumorigenesis. Following malignant transformation of cells, glucose metabolism is altered, but the importance of these metabolic changes in tumorigenesis is not entirely clear. Moreover, how metabolic changes may be linked to the inhibition of apoptosis important for tumorigenesis is not known. In this proposal, we use the biochemically powerful Xenopus egg/oocyte model system to examine the hypothesis that a cell's nutrient status can regulate the propensity of a cell to live or die. In preliminary work, we have identified a signaling pathway controlled by the metabolic state of the oocyte/egg and have demonstrated that generation of NADPH by the pentose phosphate pathway is critical for survival of these cells. The target of this regulation is an apoptotic protease, caspase 2. Specifically, inhibition of cell death in the presence of abundant NADPH, or sufficient glucose- 6-phosphate to drive operation of the pentose phosphate pathway, resulted from the inhibitory phosphorylation of caspase 2 by Calcium calmodulin-dependent kinase II (CaMKII). Conversely, activation of caspase 2 prior to cell death (following nutrient depletion) was preceded by dephosphorylation of caspase 2 at the CaMKII phosphorylation site. Consistent with these observations, a mutant variant of caspase 2 able to escape phosphorylation by CaMKII could override NADPH-mediated inhibition of apoptosis. Preliminary data indicate that metabolic regulation of caspases contribute to apoptotic control in other cell types as well. Thus, we hypothesize that the gradual exhaustion of cellular nutrients over the course of a lifetime (in the case of the oocyte) or aberrant operation of the pentose phosphate pathway during carcinogenesis, may result in an inability to drive the NADPH production required to suppress caspase 2, thereby contributing to cell death. The goal of this proposal is to understand how nutrient utilization pathways control the apoptotic protease, caspase 2.