title: α-Secretase-derived cleavage of cellular prion yields biologically active catabolites with distinct functions.
abstract: The cellular prion protein (PrP(c)) undergoes α-secretase-derived processing by disintegrins. This cleavage occurs within the 106-126 putative toxic domain of PrP(c), yielding two complementary N- and C-terminal fragments referred to as N1 and C1, respectively. Here we review our recent data showing that these two PrP(c)-derived products harbor distinct p53-dependent functions. Thus, C1 potentiates staurosporine (STS)-induced caspase-3 activation by upregulating p53 transcription, mRNA levels and activity. Conversely, N1 is protective both in vitro and in vivo. Thus, N1 inhibits STS-induced caspase-3 activation by downregulating p53 in various cell systems and protects rat retinal ganglion cells from hypoxia-induced apoptosis. Furthermore, N1 protects cells against C1-induced toxicity. Therefore, our data show that disintegrin-associated processing of PrP(c) gives rise to two fragments that display opposite effects on p53-dependent cell death and that can functionally interact.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire et Institut de Neuromédecine Moléculaire, Equipe Labellisée Fondation pour la Recherche Médicale, Sophia-Antipolis, Valbonne, France.
authors.forename: M-V
authors.initials: MV
authors.lastname: Guillot-Sestier
authors.forename: F
authors.initials: F
authors.lastname: Checler
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018621:PrPC Proteins / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018621:PrPC Proteins; D011328:Prions; D016159:Tumor Suppressor Protein p53; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D019311:Staurosporine