The C-terminal products of cellular prion protein processing, C1 and C2, exert distinct influence on p53-dependent staurosporine-induced caspase-3 activation.
The cellular prion protein (PrP(c)) undergoes various endopro-teolytic attacks within its N-terminal domain, leading to the production of C-terminal fragments (C) tethered to the plasma membrane and soluble N-terminal peptides (N). One of these cleavages occurs at position 110/111, thereby generating C1 and N1 products. We have reported that disintegrins ADAM-10, -9, and -17 participate either directly or indirectly to this proteolytic event. An alternative proteolytic event taking place around residue 90 yields C2 and N2 fragments. The putative function of these proteolytic fragments remained to be established. We have set up two novel human embryonic kidney 293 cell lines stably overexpressing either C1 or C2. We show that C1 potentiates staurosporine-induced caspase-3 activation through a p53-dependent mechanism. Thus, C1 positively controls p53 transcription and mRNA levels and increases p53-like immunoreactivity and activity. C1-induced caspase-3 activation remained unaffected by the blockade of endocytosis in HEK 293 cells and was abolished in p53-deficient fibroblasts. Conversely, overexpression of the C2 fragment did not significantly sensitize HEK 293 cells to apoptotic stimuli and did not modify p53 mRNA levels or activity. Therefore, the nature of the proteolytic cleavage taking place on PrP(c) yielded C-terminal catabolites with distinct function and could be seen as a switch mechanism controlling the function of the PrP(c) in cell survival.
Sunyach
Claire
C
Institut de Pharmacologie Moleculaire et cellulaire du CNRS, UMR6097, Université Nice-Sophia-Antipolis, Equipe labellisée Fondation pour la Recherche Médicale, 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France.
Cisse
Moustapha Alfa
MA
da Costa
Cristine Alves
CA
Vincent
Bruno
B
Checler
Frédéric
F
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018076:DNA, Complementary; D011328:Prions; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D019311:Staurosporine