Cellular prion protein sensitizes neurons to apoptotic stimuli through Mdm2-regulated and p53-dependent caspase 3-like activation.
We examined the influence of cellular prion protein (PrP(c)) in the control of cell death in stably transfected TSM1 cells. PrP(c) 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 PrP(c)- 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 PrP(c) 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.
Paitel
Erwan
E
Institut de Pharmacologie Moléculaire et Cellulaire of CNRS, UMR6097, Valbonne, France.
Fahraeus
Robin
R
Checler
Frédéric
F
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009687:Nuclear Proteins; D011328:Prions / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D019311:Staurosporine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D009687:Nuclear Proteins; D011328:Prions; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine