1. Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons
- Author
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Alves Da Costa, Cristine, Paitel, Erwan, Mattson, Mark, Amson, Robert, Telerman, Adam, Ancolio, Karine, Checler, Frédéric, Mattson, Marc, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), and École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Telencephalon ,Transcription, Genetic ,Cell Survival ,[SDV]Life Sciences [q-bio] ,Down-Regulation ,Gene Expression ,Apoptosis ,Cytochrome c Group ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Caspase 3 ,Presenilin ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bcl-2-associated X protein ,Proto-Oncogene Proteins ,Presenilin-2 ,Presenilin-1 ,Animals ,Humans ,RNA, Messenger ,Propidium iodide ,Caspase ,bcl-2-Associated X Protein ,030304 developmental biology ,Neurons ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,0303 health sciences ,Multidisciplinary ,biology ,HEK 293 cells ,Wild type ,Membrane Proteins ,Fibroblasts ,Biological Sciences ,Molecular biology ,Cell biology ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cell culture ,Caspases ,Mutation ,biology.protein ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Tumor Suppressor Protein p53 ,030217 neurology & neurosurgery - Abstract
International audience; Presenilins 1 and 2 are two homologous proteins that, when mutated, account for most early onset Alzheimer's disease. Several lines of evidence suggest that, among various functions, presenilins could modulate cell apoptotic responses. Here we establish that the overexpression of presenilin 2 (PS2) and its mutated form Asn-141-Ile-PS2 alters the viability of human embryonic kidney (HEK)293 cells as established by combined trypan blue exclusion, sodium 3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay, and propidium iodide incorporation FACS analyses. The two parent proteins increase the acetyl-DEVD-al-sensitive caspase-3-like activity in both HEK293 cells and Telencephalon specific murine neurons, modulate Bax and bcl-2 expressions, and enhance cytochrome C translocation into the cytosol. We show that overexpression of both wild-type and mutated PS2 increases p53-like immunoreactivity and transcriptional activity. We also establish that wild-type- and mutated PS2-induced caspase activation is reduced by p53 antisense approach and by pifithrin-alpha, a chemical inhibitor of p53. Furthermore, mouse fibroblasts in which the PS2 gene has been knocked out exhibited strongly reduced p53-transcriptional activity. Finally, we establish that the overexpression of both wild-type and mutated PS2 is accompanied by a drastic reduction of endogenous presenilin 1 (PS1) expression. Interestingly, pifithrin-alpha diminished endogenous PS2 immunoreactivity, whereas the inhibitor increases PS1 expression. Altogether, our data demonstrate that wild-type and familial Alzheimer's disease-linked PS2 trigger apoptosis and down-regulate PS1 expression through p53-dependent mechanisms.
- Published
- 2002
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