Cellular prion protein (PrPc) plays anti-apoptotic and anti-oxidative roles in apoptosis induced by serum deprivation in an immortalized prion protein gene (Prnp)-deficient neuronal cell line. The octapeptide repeat region (OR) and N-terminal half of the hydrophobic region (HR) of PrPc are indispensable for PrPc activity, but the mechanisms remain unclear. In the present study, elucidation of the mechanisms by which PrPC elicits the anti-oxidative activities was facilitated by evidence of stress-inducible protein 1 (STI1) mediating PrPC-dependent superoxide dismutase (SOD) activation. Immunoprecipitation revealed that PrPc was associated with STI1. The inhibitory peptides against PrPc-STI1 binding [STI1 pep. 1 and PrP (113-132)] indicated toxic activity in PrPC-expressing cells by inhibiting SOD activity but not in Prnp(-/-) cells. Furthermore, OR and N-terminal half of the HR were required for the inhibitory effect of PrP ( 113-132) but not STI1 pep. 1. These data are consistent with results established with a model where OR and N-terminal half of the HR mediate the action of STI1 upon cell survival and upregulation of SOD activity. (C) 2004 Elsevier Inc. All rights reserved.