Our previous study demonstrated that hypoxia-inducible factor-1 (HIF-1)-mediated neuroprotective effects are related to cellular prion protein (PrPc) gene (PRNP) regulation under hypoxic conditions. However, the mechanism of HIF-1 alpha-mediated PRNP gene regulation in prion-mediated neurodegenerative disorders is not clear. Transcription factor specific protein 1 (SP1) is necessary for PRNP transcription initiation, and SP1 gene expression is regulated through HIF-1 alpha activation under hypoxic conditions. Thus, we hypothesized that HIF-1 alpha-mediated neuroprotection is related to the SP1 transcription pathway as a result of PRNP gene regulation. Inhibition of SP1 expression blocked the HIF-1 alpha-mediated protective effect against prion-mediated neurotoxicity. Also, knockdown of HIF-1 alpha induced downregulation of SP1 expression and sensitivity to prion-mediated neurotoxicity, whereas upregulation of SP1 transcriptional activity lead to protection against prion-mediated neuron cell death and PRNP gene expression even in HIF-1 alpha depleted cells. This report is the first study demonstrating that HIF-1 alpha-mediated SP1 expression regulates PrPc transcription, and upregulation of SP1 induced by HIF-1 alpha plays a key role in protection from prion-mediated neurotoxicity. These studies suggest that transcription factor SP1 may be involved in the pathogenesis of prion diseases and also may be a potential therapeutic option for neurodegeneration caused by the pathological prion protein, PrPsc. (C) 2012 Elsevier Inc. All rights reserved.