| Abstract No.: | C-C3119 |
| Country: | Canada |
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| Title: | THE ROLE OF AKT, JNK, AND GSK3 SIGNALING ON PUMA INDUCTION AND NEURONAL CELL DEATH.
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| Authors/Affiliations: | 1 Kristen Pitzul*; 1 Sean Cregan;
1 Robarts Research Institute, London, ON, Canada
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| Content: | The neuronal intrinsic apoptotic pathway is activated during both chronic and acute stress, as in Parkinson’s disease and in strokes. We have identified the pro-apoptotic Bcl-2 family member Puma as a key regulator of apoptosis in response to diverse neuronal insults. However, the mechanisms regulating Puma induction have yet to be clearly defined. Objective: In the present study we have investigated the role of Akt/PI3K, JNK, and GSK3 signaling on Puma induction and neuronal cell death. Materials and Methods: Cerebellar granule neurons (CGNs) were isolated from 7 day old mouse pups and incubated in survival medium containing 25mM potassium levels. Apoptosis was induced using a serum-potassium deprivation model. Pharmacological agents IGF, SP600125, and SB415286 were used to promote or inhibit the AKT, JNK, and GSK3 pathways, respectively. Results: We have determined that SP600125, SB415286, and IGF suppress transcriptional induction of Puma and subsequent mitochondrial permeabilization, caspase activation, and neuronal cell death. Finally, we have determined that Puma-deficient neurons are markedly resistant to potassium-withdrawal-induced apoptosis. Conclusion: Taken together our results suggest that activation of AKT/PI3K signaling, as well as inhibition of JNK and GSK3 signaling, protects against neuronal apoptosis by promoting the transcriptional induction of Puma.
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