The C-terminal fragment of presenilin 2 triggers p53-mediated staurosporine-induced apoptosis, a function independent of the presenilinase-derived N-terminal counterpart

Cristine Alves Da Costa, Mark P. Mattson, Karine Ancolio, Frédéric Checler

Research output: Contribution to journalArticlepeer-review

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 Aβ 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-α, 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.

Original languageEnglish (US)
Pages (from-to)12064-12069
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number14
DOIs
StatePublished - Apr 4 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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