Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 12, Pages 10061-10066Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M211580200
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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-alpha, 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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