p53-Dependent transcriptional control of cellular prion by presenilins.
The presenilin-dependent gamma-secretase processing of the beta-amyloid precursor protein (betaAPP) conditions the length of the amyloid beta peptides (Abeta) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilin-mediated epsilon-secretase cleavage, generates intracellular betaAPP-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 (PrP(c)) by a gamma-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrP(c) involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrP(c) transcription. Furthermore, we show that p53 directly binds to the PrP(c) promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrP(c) 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 betaAPP metabolism to the physiology of PrP(c).
Vincent
Bruno
B
Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097 Centre National de la Recherche Scientifique/Université de Nice-Sophia-Antipolis, 06560 Valbonne, France. vincentb@ipmc.cnrs.fr
Sunyach
Claire
C
Orzechowski
Hans-Dieter
HD
St George-Hyslop
Peter
P
Checler
Frédéric
F
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000172:deficiency / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed / Q000379:methods; D053763:Presenilins / Q000172:deficiency / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053763:Presenilins; D011328:Prions; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D053829:Amyloid Precursor Protein Secretases