title: IGF-1-induced enhancement of PRNP expression depends on the negative regulation of transcription factor FOXO3a.
abstract: 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.
authors: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors: Ting
authors: T
authors: Liu
authors: Wenjing
authors: W
authors: Yi
authors: Boya
authors: B
authors: Feng
authors: Zheng
authors: Z
authors: Zhou
authors: Gengfu
authors: G
authors: Xiao
mesh_terms: D001483:Base Sequence; D015536:Down-Regulation / Q000187:drug effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
references: Neuropeptides. 2002 Apr-Jun;36(2-3):209-20
references: 12359511
references: Dev Dyn. 2010 May;239(5):1405-12
references: 20140911
references: Biochem J. 1998 Sep 1;334 ( Pt 2):423-9
references: 9716501
references: Trends Neurosci. 2003 Aug;26(8):404-6
references: 12900169
references: Biochem Biophys Res Commun. 2005 Jul 22;333(1):95-100
references: 15936714
references: J Biol Chem. 2009 Jan 9;284(2):1291-301
references: 18990686
references: J Biol Chem. 2004 Jul 9;279(28):28873-9
references: 15126506
references: J Neurosci. 2000 Nov 15;20(22):8435-42
references: 11069951
references: Cell. 2004 Apr 16;117(2):225-37
references: 15084260
references: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7
references: 15220471
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: Cell Mol Life Sci. 2005 Feb;62(3):320-43
references: 15723168
references: Am J Pathol. 1986 Jan;122(1):1-5
references: 3079955
references: Cancer Sci. 2007 Jun;98(6):838-43
references: 17470130
references: Mol Neurobiol. 1996 Oct;13(2):155-83
references: 8938649
references: Oncogene. 2008 Apr 7;27(16):2276-88
references: 18391970
references: Cell Mol Life Sci. 2009 Dec;66(23):3809-20
references: 19756378
references: Trends Biochem Sci. 2000 Nov;25(11):555-60
references: 11084368
references: J Biol Chem. 2009 Oct 23;284(43):29454-61
references: 19720829
references: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references: 9811807
references: J Clin Invest. 2006 Sep;116(9):2464-72
references: 16906224
references: Mol Neurobiol. 2002 Aug;26(1):1-12
references: 12392052
references: J Biol Chem. 2009 Mar 13;284(11):6716-24
references: 19129193
references: Exp Neurol. 1994 Dec;130(2):407-10
references: 7867769
references: Int J Mol Med. 2012 Nov;30(5):1069-74
references: 22895829
references: Neurodegeneration. 1994 Dec;3(4):331-40
references: 7842304
references: Horm Res. 1996;45 Suppl 1:5-7
references: 8805018
references: FEBS Lett. 2002 Feb 13;512(1-3):25-8
references: 11852045
references: Nature. 2002 Sep 19;419(6904):316-21
references: 12239572
references: Am J Pathol. 1999 Nov;155(5):1723-30
references: 10550328
references: J Clin Invest. 2005 Sep;115(9):2382-92
references: 16100571
references: J Biol Chem. 2005 Apr 1;280(13):12096-102
references: 15632117
references: Eur J Neurosci. 2004 Apr;19(8):2056-68
references: 15090033
references: J Biol Chem. 2009 Feb 13;284(7):4582-93
references: 19064990
references: J Neurosci Res. 2005 Jun 15;80(6):887-94
references: 15884019
references: Cell Mol Neurobiol. 2004 Apr;24(2):257-68
references: 15176439
references: Virology. 2009 Mar 15;385(2):343-50
references: 19138779
references: Neurosci Lett. 2006 May 29;400(1-2):58-62
references: 16520000
references: Biochem Biophys Res Commun. 1993 Nov 15;196(3):1163-9
references: 7902706
references: Mol Neurobiol. 1996 Dec;13(3):227-55
references: 8989772
references: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10412-7
references: 10973497
references: Cell. 1993 Jul 2;73(7):1339-47
references: 8100741
references: EMBO J. 2002 Jul 1;21(13):3317-26
references: 12093733
references: Mol Biotechnol. 2002 Oct;22(2):165-78
references: 12405264
references: Br J Cancer. 2008 Mar 25;98(6):1068-75
references: 18319717
references: EMBO J. 2004 Dec 8;23(24):4802-12
references: 15538382
references: Science. 1982 Apr 9;216(4542):136-44
references: 6801762
references: Free Radic Biol Med. 2001 May 15;30(10):1137-44
references: 11369504
references: J Biol Chem. 2008 Mar 28;283(13):8211-7
references: 18195003
references: Antioxid Redox Signal. 2011 Feb 15;14(4):579-92
references: 20673124
references: Antioxid Redox Signal. 2008 Apr;10(4):661-78
references: 18162053
references: Brain Res Dev Brain Res. 1996 Aug 20;95(1):44-54
references: 8873975
references: Neuron. 1995 Mar;14(3):509-17
references: 7695897
references: Mech Ageing Dev. 2005 Jan;126(1):209-15
references: 15610780
references: Genomics. 1998 Jan 15;47(2):187-99
references: 9479491
references: Nat Rev Mol Cell Biol. 2005 Dec;6(12):971-6
references: 16227974
references: Mamm Genome. 2001 Jun;12(6):416-25
references: 11353388
references: J Biol Chem. 2003 Sep 19;278(38):35959-67
references: 12857750
references: Nature. 1978 Apr 27;272(5656):827-9
references: 205798