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The Journal of Neuroscience, May 20, 2009, 29(20):6752-6760; doi:10.1523/JNEUROSCI.0789-09.2009

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 Previous Article

Cellular/Molecular
p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

Bruno Vincent,1,2 Claire Sunyach,1,2 Hans-Dieter Orzechowski,3 Peter St George-Hyslop,4,5 and Frédéric Checler1,2

1Institut de Pharmacologie Moléculaire et Cellulaire and 2Institut de Neuro-Médecine Moléculaire, Unité Mixte de Recherche 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 06560 Valbonne, France, 3Institute of Clinical Pharmacology and Toxicology, Charité-Universitaetsmedizin Berlin, 10117 Berlin, Germany, 4Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto and University Health Network Toronto Western Hospital Research Institute, Toronto, Ontario M5S 3H2, Canada, and 5Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 OXY, United Kingdom

Correspondence should be addressed to either Bruno Vincent or Frédéric Checler, Institut de Neuromédecine Moléculaire, UMR6097 CNRS/UNSA, 660 route des lucioles, 06560 Valbonne, France, Email: vincentb{at}ipmc.cnrs.fr or Email: checler{at}ipmc.cnrs.fr

The presenilin-dependent {gamma}-secretase processing of the β-amyloid precursor protein (βAPP) conditions the length of the amyloid β peptides (Aβ) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilin-mediated {varepsilon}-secretase cleavage, generates intracellular βAPP-derived fragments named amyloid intracellular domains (AICDs) that regulate the transcription of several genes. We establish that presenilins control the transcription of cellular prion protein (PrPc) by a {gamma}-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrPc involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrPc transcription. Furthermore, we show that p53 directly binds to the PrPc promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrPc by the oncogene p53 that is directly driven by presenilin-dependent formation of AICD. Furthermore, it adds support to previous reports linking secretase activities involved in βAPP metabolism to the physiology of PrPc.

Received Feb. 16, 2009; revised March 30, 2009; accepted April 17, 2009.

Correspondence should be addressed to either Bruno Vincent or Frédéric Checler, Institut de Neuromédecine Moléculaire, UMR6097 CNRS/UNSA, 660 route des lucioles, 06560 Valbonne, France, Email: vincentb{at}ipmc.cnrs.fr or Email: checler{at}ipmc.cnrs.fr






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