Abstract
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).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / deficiency
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Amyloid beta-Protein Precursor / genetics
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Animals
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Brain / metabolism
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Cells, Cultured
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Chromatin Immunoprecipitation / methods
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Cyclin-Dependent Kinase Inhibitor p19 / deficiency
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Cyclin-Dependent Kinase Inhibitor p19 / genetics
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Dipeptides / pharmacology
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Humans
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Mice
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Mice, Knockout
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Mutagenesis, Site-Directed / methods
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Presenilins / deficiency
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Presenilins / metabolism*
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Prions / metabolism*
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Protein Structure, Tertiary / genetics
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RNA, Messenger / metabolism
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Transfection / methods
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Amyloid beta-Protein Precursor
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Aplp2 protein, mouse
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Cdkn2d protein, mouse
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Cyclin-Dependent Kinase Inhibitor p19
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Dipeptides
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Enzyme Inhibitors
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N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
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Presenilins
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Prions
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RNA, Messenger
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Tumor Suppressor Protein p53
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Amyloid Precursor Protein Secretases