p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex.
Nicastrin (NCT) is a component of the presenilin (PS)-dependent gamma-secretase complexes that liberate amyloid beta-peptides from the beta-Amyloid Precursor Protein. Several lines of evidence indicate that the members of these complexes could also contribute to the control of cell death. Here we show that over-expression of NCT increases the viability of human embryonic kidney (HEK293) cells and decreases staurosporine (STS)- and thapsigargin (TPS)-induced caspase-3 activation in various cell lines from human and neuronal origins by Akt-dependent pathway. NCT lowers p53 expression, transcriptional activity and promoter transactivation and reduces p53 phosphorylation. NCT-associated protection against STS-stimulated cell death was completely abolished by p53 deficiency. Conversely, the depletion of NCT drastically enhances STS-induced caspase-3 activation and p53 pathway and favored p53 nuclear translocation. We examined whether NCT protective function depends on PS-dependent gamma-secretase activity. First, a 29-amino acid deletion known to reduce NCT-dependent amyloid beta-peptide production did not affect NCT-associated protective phenotype. Second, NCT still reduces STS-induced caspase-3 activation in fibroblasts lacking PS1 and PS2. Third, the gamma-secretase inhibitor DFK167 did not affect NCT-mediated reduction of p53 activity. Altogether, our study indicates that NCT controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways and that this function remains independent of the activity and molecular integrity of the gamma-secretase complexes.
Pardossi-Piquard
Raphaëlle
R
Institut de Pharmacologie Moléculaire et Cellulaire and Institut de NeuroMédecine Moléculaire of Centre National de la Recherche Scientifique, Equipe labellisée Fondation pour la Recherche Médicale, Valbonne, France.
Dunys
Julie
J
Giaime
Emilie
E
Guillot-Sestier
Marie-Victoire
MV
St George-Hyslop
Peter
P
Checler
Frédéric
F
Alves da Costa
Cristine
C
D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D008562:Membrane Glycoproteins; D053763:Presenilins; D016159:Tumor Suppressor Protein p53; C413604:nicastrin protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases