SUMMARY Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII) mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis, in a novel mechanism of CaMKII activation. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca2+ to activate CaMKII in a calmodulin-dependent manner. Furthermore, we show that CoA inhibits apoptosis not only in X. laevis oocytes, but also in Murine oocytes. These findings uncover a novel mechanism of CaMKII regulation by metabolism and further highlight the importance of metabolism in preserving oocyte viability.

The anti-apoptotic function and tumor-associated expression of HSP70 is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3−/− (Hsp70−/−) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70−/− murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immune deficient hosts as efficiently as WT transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70−/− bone marrow and progression of B cell leukemogenesis in vivo revealed no differences in disease onset or survival rates and Eμ-Myc driven lymphoma in Hsp70−/− mice was phenotypically indistinguishable from WT Eμ-Myc mice. However, Hsp70−/− E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6J immune competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8+ T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.

Background:In the basal state, oocytes produce lactate from G6P even in the presence of oxygen. Results: Addition of G6P to egg extracts inhibits PP1, preventing dephosphorylation/inactivation of CaMKII and initiation of apoptotic pathways. Conclusion: Normal oocyte metabolism suppresses apoptosis by inhibiting PP1 and activating CaMKII. Significance: These mechanistic insights suggest potential targets for modulating cell death.

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