Presenilin-Dependent -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease
| Autor: | Bruno Vincent, Nicole Boyer, Raphaëlle Pardossi-Piquard, Nadège Girardot, Cristine Alves da Costa, Peter St George-Hyslop, T. Kawarai, Claire Sunyach, Frédéric Checler, Jean Sevalle |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Transcriptional Activation Transcription Genetic Amyloid Nerve Tissue Proteins Biology medicine.disease_cause Presenilin Cell Line Amyloid beta-Protein Precursor Transactivation Alzheimer Disease Endopeptidases Presenilin-2 mental disorders Presenilin-1 medicine Aspartic Acid Endopeptidases Humans Promoter Regions Genetic Gamma secretase Aged Mutation Cell Death Caspase 3 General Neuroscience HEK 293 cells Brain Membrane Proteins Articles Middle Aged Peptide Fragments Protein Structure Tertiary Cell biology Enzyme Activation Case-Control Studies Caspases Immunology biology.protein Female Amyloid Precursor Protein Secretases Tumor Suppressor Protein p53 Amyloid precursor protein secretase Intracellular |
| Zdroj: | Journal of Neuroscience. 26:6377-6385 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains. |
| Databáze: | OpenAIRE |
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