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

Ting Liu,Boya Feng,Wenjing Yi,Gengfu Xiao,Zheng Zhou,Jörg Tatzelt

doi:10.1371/journal.pone.0071896

Ting Liu, Boya Feng + Show 4 more

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https://doi.org/10.1371/journal.pone.0071896

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Journal: PLoS ONE	Publication Date: Aug 14, 2013
Citations: 16	License type: CC BY 4.0

Affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences

Abstract

The conformational conversion of the cellular prion protein (PrPC) into its β-sheet-rich scrapie isoform (PrPSc) causes fatal prion diseases, which are also called transmissible spongiform encephalopathies (TSEs). Recent studies suggest that the expression of PrPC 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 PrPC and for future therapeutic approaches to human TSEs.

Highlights

The conformational conversion of the cellular prion protein (PrPC) into its b-sheet-rich scrapie isoform (PrPSc) causes fatal prion diseases, which are called transmissible spongiform encephalopathies (TSEs).The TSEs include scrapie, bovine spongiform encephalopathy (BSE), and human Creutzfeld-Jacob disease (CJD) [1,2]
To further identify whether the insulin-like growth factor 1 (IGF-1)-induced elevation of the PrP protein occurs at the transcriptional level, real-time PCR was conducted to compare the level of PrP mRNA with that of the control GAPDH mRNA in both the HeLa and SH-SY5Y cell lines
Conflicting results have been published by Lasmezas, C. and Castelnau, P. [17,18], our results confirm that 100 ng/ml IGF-1 treatment does increase the PrP protein and mRNA levels in the SH-SY5Y and HeLa cell lines, both of which are derived from Homo sapiens

Summary

Introduction

The conformational conversion of the cellular prion protein (PrPC) into its b-sheet-rich scrapie isoform (PrPSc) causes fatal prion diseases, which are called transmissible spongiform encephalopathies (TSEs).The TSEs include scrapie, bovine spongiform encephalopathy (BSE), and human Creutzfeld-Jacob disease (CJD) [1,2]. Studies have demonstrated that the expression of cellular PrP is essential to the development of TSEs because Prnp knock-out mice are resistant to TSEs [7]. Individuals who have a higher level of PRNP expression might be expected to have shorter incubation periods following iatrogenic exposure to human prions or exposure to BSE. The up- and down-regulation of human PRNP expression appear to be critical for the pathogenesis of human TSEs, such as CJD and fatal familial insomnia (FFI)

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