Journal of Biological Chemistry
Volume 278, Issue 12, 21 March 2003, Pages 10061-10066
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MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Cellular Prion Protein Sensitizes Neurons to Apoptotic Stimuli through Mdm2-regulated and p53-dependent Caspase 3-like Activation*

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We examined the influence of cellular prion protein (PrPc) in the control of cell death in stably transfected TSM1 cells. PrPc expression enhanced staurosporine-stimulated neuronal toxicity and DNA fragmentation, caspase 3-like activity and immunoreactivity, and p53 immunoreactivity and transcriptional activities. Caspase activation was reduced by the chemical inhibitor of p53, pifithrin-α, as well as by PrPc- or p53-antisense approaches but remained insensitive to the Fyn kinase inhibitor PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine). We establish that PrPc controls p53 at a post-transcriptional level and is reversed by Mdm2 transfection and p38 MAPK inhibitor. We propose that endogenous cellular prion protein sensitizes neurons to apoptotic stimuli through a p53-dependent caspase 3-mediated activation controlled by Mdm2 and p38 MAPK.

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Published, JBC Papers in Press, January 14, 2003, DOI 10.1074/jbc.M211580200

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This work was supported in part by the Groupe d'Intérél-Scientifique “Infections à prions” and by the CNRS and by INSERM.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.