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J. Biol. Chem., Vol. 282, Issue 14, 10516-10525, April 6, 2007

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p53-dependent Aph-1 and Pen-2 Anti-apoptotic Phenotype Requires the Integrity of the -Secretase Complex but Is Independent of Its Activity^*

Julie Dunys¹, Toshitaka Kawarai, Jean Sevalle, Virginia Dolcini, Peter St. George-Hyslop, Cristine Alves Da Costa², and Frédéric Checler³

From the Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097 CNRS/UNSA, Equipe labellisée, Fondation pour la Recherche Médicale, 660 Route des Lucioles, 06560 Valbonne, France and the Center for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto and Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario M5S 3H2, Canada

The presenilin-dependent -secretase activity, which is responsible for the generation of amyloid -peptide, is a high molecular weight complex composed of at least four components, namely, presenilin-1 (or presenilin-2), nicastrin, Aph-1, and Pen-2. Previous data indicated that presenilins, which are thought to harbor the catalytic core of the complex, also control p53-dependent cell death. Whether the other components of the -secretase complex could also modulate the cell death process in mammalian neurons remained to be established. Here, we examined the putative contribution of Aph-1 and Pen-2 in the control of apoptosis in TSM1 cells from a neuronal origin. We show by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and DNA fragmentation analyses that the overexpression of Aph-1a, Aph-1b, or Pen-2 drastically lowered staurosporine-induced cellular toxicity. In support of an apoptosis rather than necrosis process, Aph-1 and Pen-2 also lower staurosporine- and etoposide-induced caspase-3 expression and diminished caspase-3 activity and poly(ADP-ribose) polymerase inactivation. The Aph-1 and Pen-2 anti-apoptotic phenotype was associated with a drastic reduction of p53 expression and activity and lowered p53 mRNA transcription. Furthermore, the Aph-1- and Pen-2-associated reduction of staurosporine-induced caspase-3 activation was fully abolished by p53 deficiency. Conversely, Aph-1a, Aph-1b, and Pen-2 gene inactivation increases both caspase-3 activity and p53 mRNA levels. Finally, we show that Aph-1 and Pen-2 did not trigger an anti-apoptotic response in cells devoid of presenilins or nicastrin, whereas the protective response was still observed in fibroblasts devoid of -amyloid precursor protein and amyloid precursor protein like-protein 2. Furthermore, Aph-1- and Pen-2-associated protection against staurosporine-induced caspase-3 activation was not affected by the -secretase inhibitors N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester and difluoromethylketone. Altogether, our study indicates that Aph-1 and Pen-2 trigger an anti-apoptotic response by lowering p53-dependent control of caspase-3. Our work also demonstrates that this phenotype is strictly dependent on the molecular integrity of the -secretase complex but remains independent of the -secretase catalytic activity.

Received for publication, December 18, 2006

^* This work was supported in part by the CNRS, by an European Union contract LSHM-CT-2003-503330 (APOPIS), by the Fondation pour la Recherche Médicale, and by Unis pour la Recherche sur la Maladie d'Alzheimer (URMA). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by an APOPIS (Abnormal proteins in the pathogenesis of neuro degenerative disorders) -integrated project.

² To whom correspondence may be addressed: Tel.: 33-4-93-95-77-59; Fax: 33-4-93-95-77-08; E-mail: acosta{at}ipmc.cnrs.fr. ³ To whom correspondence may be addressed: Tel.: 33-4-93-95-77-60; Fax: 33-4-93-95-77-08; E-mail: checler{at}ipmc.cnrs.fr.

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