Cellular prion protein (PrPC) expression can be regulated by heat-shock stress, and we designed the present study to determine whether hypoglycemia could affect PrPC expression. RT-PCR and Western blotting were used to measure the expression of PrPC and heat-shock protein (Hsp70) in mouse neuroblastoma (N18) cells cultured 3 hr to 3 days in media deprived of 97.5% (L) or 75% (M) of its glucose. Hypoglycemia caused a concomitant time-dependent and glucose dose-dependent increase in PrPC and Hsp70. In addition, hypoglycemia also increased phosphorylated c-Jun N-terminal kinase (JNK) protein levels in a time-dependent manner. The upregulation of PrPC and Hsp70 under hypoglycemic conditions was disrupted by the specific JNK inhibitor SP600125. It was also found from in vitro studies that hypoglycemic conditions induced higher levels of PrPC promoter activity in PrPC promoters containing a heat-shock element (HSE) than in PrPC promoters lacking HSE. We propose that hypoglycemia-increased PrPC expression might be due to JNK phosphorylation of a heat-shock transcriptional factor, which then interacts with HSE in the promoter of PrPC.
