title: Transcriptional regulation of specific protein 1 (SP1) by hypoxia-inducible factor 1 alpha (HIF-1α) leads to PRNP expression and neuroprotection from toxic prion peptide.
abstract: 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-1α-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-1α activation under hypoxic conditions. Thus, we hypothesized that HIF-1α-mediated neuroprotection is related to the SP1 transcription pathway as a result of PRNP gene regulation. Inhibition of SP1 expression blocked the HIF-1α-mediated protective effect against prion-mediated neurotoxicity. Also, knockdown of HIF-1α 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-1α depleted cells. This report is the first study demonstrating that HIF-1α-mediated SP1 expression regulates PrPc transcription, and upregulation of SP1 induced by HIF-1α 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.
authors.affiliation: Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, South Korea.
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics* / Q000494:pharmacology*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C512656:PRNP protein, human; D010446:Peptide Fragments; D000072002:Prion Proteins; D011328:Prions; D016329:Sp1 Transcription Factor; C082632:prion protein (106-126)