| Abstract No.: | C-C3113 |
| Country: | Canada |
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| Title: | P53-INDEPENDENT REGULATION OF PUMA INDUCTION BY P53 FAMILY MEMBERS, P63 AND P73. |
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| Authors/Affiliations: | 1 Patrick Swan*;
1 Robarts Research Institute, London, ON, Canada
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| Content: | Objectives: Oxidative stress and ER dysfunction have been implicated as key triggers of neuronal apoptosis in acute and chronic neurodegenerative conditions. Recent work in our lab has shown that p53 up-regulated mediator of apoptosis (PUMA) is required for oxidative- and ER-stress induced neuronal cell death. In the present study we demonstrate that oxidative- and ER-stressors induce PUMA expression and neuronal cell death through a p53-independent mechanism. Since the p53 family members, p63 and p73, are known to transactivate certain p53-responsive genes, we examined the possibility that these family members might co-operate with p53 or compensate for its loss in this context. Materials & Methods: Cortical or cerebellar granule neurons derived from wildtype, p53-/- or p63-/- mice were exposed to agents known to induce oxidative stress, ER-stress or DNA damage. Puma expression (mRNA levels) was determined by quantitative RT-PCR and apoptosis was assessed by nuclear morphology and caspase-3 activity assay. Results: Wildtype and p63-deficient cortical neurons exhibited similar levels of PUMA induction and neuronal apoptosis in response to oxidative and ER-stress. Furthermore, neuronal cell death was not significantly reduced in neurons deficient for both p53 and p63 suggesting that p63 does not mediate the p53-independent induction of PUMA and neuronal cell death. Finally, we found that ectopic expression of a dominant-negative isoform of p73 (DNp73a) failed to protect against ER-stress induced apoptosis in p53-/- neurons. Conclusions: These results suggest that p63 and p73 do not mediate the p53-independent pathway regulating Puma induction and cell death in response to oxidative or ER dysfunction. |
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