α-Secretase-derived cleavage of cellular prion yields biologically active catabolites with distinct functions

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.