The Journal of neuroscience, 2009-05, Vol.29 (20), p.6752-6760
2009
Details
- Autor(en) / Beteiligte
- Titel
- p53-Dependent Transcriptional Control of Cellular Prion by Presenilins
- Ist Teil von
- The Journal of neuroscience, 2009-05, Vol.29 (20), p.6752-6760
- Ort / Verlag
- United States: Soc Neuroscience
- Erscheinungsjahr
- 2009
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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).
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0270-6474eISSN: 1529-2401DOI: 10.1523/JNEUROSCI.0789-09.2009Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6665908
- Format
- –
- Schlagworte
- Amyloid beta-Protein Precursor, Amyloid beta-Protein Precursor - deficiency, Amyloid beta-Protein Precursor - genetics, Amyloid Precursor Protein Secretases, Amyloid Precursor Protein Secretases - genetics, Amyloid Precursor Protein Secretases - metabolism, Animals, Brain, Brain - metabolism, Cells, Cultured, Cellular Biology, Chromatin Immunoprecipitation, Chromatin Immunoprecipitation - methods, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase Inhibitor p19 - deficiency, Cyclin-Dependent Kinase Inhibitor p19 - genetics, Dipeptides - pharmacology, Embryo, Mammalian, Enzyme Inhibitors, Enzyme Inhibitors - pharmacology, Fibroblasts, Fibroblasts - drug effects, Fibroblasts - metabolism, gamma-Aminobutyric Acid, Gene Expression Regulation, Gene Expression Regulation - drug effects, Gene Expression Regulation - genetics, Humans, Life Sciences, Mice, Mice, Knockout, Mutagenesis, Site-Directed, Mutagenesis, Site-Directed - methods, Neurons and Cognition, Presenilins, Presenilins - deficiency, Presenilins - metabolism, Prions, Prions - metabolism, Protein Structure, Tertiary, Protein Structure, Tertiary - genetics, RNA, Messenger, RNA, Messenger - metabolism, Transfection, Transfection - methods, Triglycerides, Tumor Suppressor Protein p53, Tumor Suppressor Protein p53 - deficiency, Tumor Suppressor Protein p53 - metabolism