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The conformational conversion of the cellular prion protein (PrP C ) into its β-sheet-rich scrapie isoform (PrP Sc ) causes fatal prion diseases, which are also called transmissible spongiform encephalopathies (TSEs). Recent studies suggest that the expression of PrP C  by the  PRNP  gene is crucial for the development of TSEs. Therefore, the identification of the exogenous and endogenous stimulating factors that regulate  PRNP  expression would help to understand the pathogenesis of TSEs. Here, we demonstrate that forkhead box O3a (FOXO3a) negatively regulates  PRNP  expression by binding to the  PRNP  promoter, which is negatively regulated by insulin-like growth factor 1 (IGF-1). Our results show that the IGF-1-induced enhancement of  PRNP  mRNA and protein levels is due to the activation of the PI3K-Akt signaling pathway. The activation of Akt then induces the phosphorylation of FOXO3a, leading to its translocation from the nucleus to the cytoplasm and preventing its binding to the  PRNP  promoter. Treatment with the PI3K-Akt inhibitor LY294002 induces the nuclear retention of FOXO3a, which leads to a decrease in  PRNP  expression. We present a new IGF-1-PI3K-Akt-FOXO3a pathway, which influences  PRNP  expression. The results of this work are vital for understanding the function of PrP C  and for future therapeutic approaches to human TSEs.

IGF-1-Induced Enhancement of PRNP Expression Depends on the Negative Regulation of Transcription Factor FOXO3a