Journal of Biological Chemistry
Volume 282, Issue 3, 19 January 2007, Pages 1956-1963
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Molecular Basis of Cell and Developmental Biology
The C-terminal Products of Cellular Prion Protein Processing, C1 and C2, Exert Distinct Influence on p53-dependent Staurosporine-induced Caspase-3 Activation*

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The cellular prion protein (PrPc) 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 PrPc yielded C-terminal catabolites with distinct function and could be seen as a switch mechanism controlling the function of the PrPc in cell survival.

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This work was supported by grants from the Abnormal Proteins in the Pathogenesis of Neurodegenerative Diseases integrated project (Grant PL 503330), the Groupement d'Intérêt Scientifique: infections à prions, the Fondation pour la Recherche Médicale, and the Fondation pour la Recherche sur le Cerveau. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

A recipient of a fellowship from the Fondation pour la Recherche Médicale. Now supported by the Association France Alzheimer.