title: The C-terminal fragment of presenilin 2 triggers p53-mediated staurosporine-induced apoptosis, a function independent of the presenilinase-derived N-terminal counterpart.
abstract: Mutations on presenilins are responsible for most of familial forms of Alzheimer's disease. These holoproteins undergo rapid maturation by presenilinase mainly in the endoplasmic reticulum, leading to the production of N- and C-terminal fragments. We show first that overexpression of the presenilinase-derived maturation product of presenilin 2 (CTF-PS2) increases Abeta recovery, the production of which is almost abolished by a caspase 3 inhibitor and increased by staurosporine. This and the observation that the apoptotic inducer staurosporine enhances CTF-PS2 degradation clearly link CTF-PS2 to apoptotic cascade effectors. This prompted us to analyze the putative ability of CTF-PS2 to modulate cell death. CTF-PS2 overexpression decreases cell viability and augments both caspase 3 activity and immunoreactivity. This is accompanied by lowered bcl2-like immunoreactivity and increased poly(ADP-ribose) polymerase cleavage and cytochrome c translocation into the cytosol. Interestingly, CTF-PS2-induced caspase 3 activation is prevented by pifithrin-alpha, a selective blocker of p53 transcriptional activity. On line with the latter data, CTF-PS2 drastically increases p53 immunoreactivity and transcriptional activity. Of most interest is our observation that CTF-PS2 expression also triggers increased caspase 3 activity and immunoreactivity in fibroblasts in which presenilins had been deleted. Therefore, CTF-PS2 could modulate cell death out of the NTF/CTF heterodimeric complex thought to correspond to the biologically functional entity. This is the first direct demonstration that CTF-PS2 could exhibit some of its functions in the absence of the presenilin 2 N-terminal fragment (NTF-PS2) counterpart derived from the presenilinase cleavage.
authors.affiliation: Intitut de Pharmacologie Moléculaire et Cellulaire of CNRS, UMR6097, Valbonne 06560, France.
authors.forename: Cristine
authors.initials: C
authors.lastname: Alves da Costa
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Karine
authors.initials: K
authors.lastname: Ancolio
authors.forename: Frederic
authors.initials: F
authors.lastname: Checler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics; D010641:Phenotype; D053766:Presenilin-2; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine