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First published online November 4, 2009
doi: 10.1242/10.1242/jcs.051169

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p53-dependent control of transactivation of the Pen2 promoter by presenilins

¹ Institut de Pharmacologie Moléculaire et Cellulaire of Centre National de la Recherche Scientifique and Institut de NeuroMédecine Moléculaire, Equipe labellisée Fondation pour la Recherche Médicale, Valbonne, France
² Cogniscience, Research Triangle Park, NC 27709, USA
³ Medical Genetics Unit, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusalem 91031, Israel
⁴ Neurodegeneration Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
⁵ Institute for Biomedical Research and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen 361005, China

^* Authors for correspondence (checler{at}ipmc.cnrs.fr; acosta{at}ipmc.cnrs.fr)

Accepted 18 August 2009

The senile plaques found in the brains of patients with Alzheimer's disease are mainly due to the accumulation of amyloid β-peptides (Aβ) that are liberated by -secretase, a high molecular weight complex including presenilins, PEN-2, APH-1 and nicastrin. The depletion of each of these proteins disrupts the complex assembly into a functional protease. Here, we describe another level of regulation of this multimeric protease. The depletion of both presenilins drastically reduces Pen2 mRNA levels and its promoter transactivation. Furthermore, overexpression of presenilin-1 lowers Pen2 promoter transactivation, a phenotype abolished by a double mutation known to prevent presenilin-dependent -secretase activity. PEN-2 expression is decreased by depletion of β-amyloid precursor protein (APP) and increased by the APP intracellular domain (AICD). We show that AICD and APP complement for Pen2 mRNA levels in APP/APLP1-2 knockout fibroblasts. Interestingly, overexpression of presenilin-2 greatly increases Pen2 promoter transactivation. The opposite effect triggered by both presenilins was reminiscent of our previous study, which showed that these two proteins elicit antagonistic effects on p53. Therefore, we examined the contribution of p53 on Pen2 transcription. Pen2 promoter transactivation, and Pen2 mRNA and protein levels were drastically reduced in p53^–/– fibroblasts. Furthermore, PEN-2 expression could be rescued by p53 complementation in p53- and APP-deficient cells. Interestingly, PEN-2 expression was also reduced in p53-deficient mouse brain. Overall, our study describes a p53-dependent regulation of PEN-2 expression by other members of the -secretase complex, namely presenilins.

Key words: Alzheimer disease, Presenilins, PEN-2, AICD, p53, Transcription

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