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p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

The presenilin-dependent γ-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 ε-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 γ-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.