title: FoxO3a is activated and executes neuron death via Bim in response to β-amyloid.
abstract: The molecules that mediate death of selective neurons in Alzheimer's disease (AD) are mostly unknown. The Forkhead transcription factor FoxO3a has emerged as an important mediator of cell fate including apoptosis. When phosphorylated by Akt, it is localized in the cytosol as an inactive complex bound with 14-3-3 protein. For activation and localization of FoxO3a in the nucleus, further modifications are required, such as phosphorylation by mammalian sterile 20-like kinase 1 (MST1) and arginine methylation by protein arginine methyltransferase1. We report here that Akt-mediated phosphorylation of FoxO3a is diminished in neurons exposed to oligomeric β-amyloid (Aβ), in vitro and in vivo. We also find that oligomeric Aβ activates FoxO3a by MST1 phosphorylation and arginine methylation in primary cultures of hippocampal and cortical neurons. Moreover, FoxO3a translocates from the cytosol to nucleus in cultured neurons in response to Aβ. Most importantly, the nuclear redistribution of FoxO3a is significantly increased in Aβ-overexpressing AβPPswe-PS1dE9 mice and Aβ-infused rat brains. We further find that FoxO3a is essential for loss of neurons and neural networks in response to Aβ. Recent reports implicate Bim, a pro-apoptotic member of Bcl-2 family, in neuron death in AD, as a key target of this transcription factor. We show that Bim is a direct target of FoxO3a in Aβ-treated neurons. Our findings thus indicate that FoxO3a is activated, translocated to the nucleus and mediates neuron death via Bim in response to Aβ toxicity.
authors: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors: P
authors: P
authors: Sanphui
authors: S C
authors: SC
authors: Biswas
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt
references: J Neurosci. 2005 Sep 14;25(37):8349-58
references: 16162916
references: Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424-8
references: 1065897
references: Ann N Y Acad Sci. 2008 Dec;1147:335-47
references: 19076455
references: Cell. 1999 Mar 19;96(6):857-68
references: 10102273
references: J Biol Chem. 2002 Dec 20;277(51):49511-6
references: 12388545
references: Nature. 2009 Feb 19;457(7232):981-9
references: 19225519
references: BMC Neurosci. 2004 Nov 29;5:48
references: 15569384
references: Genomics. 1998 Jan 15;47(2):187-99
references: 9479491
references: J Cell Biol. 1998 Oct 19;143(2):457-67
references: 9786955
references: J Exp Med. 2006 Jul 10;203(7):1657-63
references: 16801400
references: Biochem Biophys Res Commun. 2012 Mar 2;419(1):49-53
references: 22326868
references: J Alzheimers Dis. 2012;28(4):765-9
references: 22112551
references: J Neurosci. 2003 Feb 15;23(4):1237-45
references: 12598612
references: Age (Dordr). 2013 Feb;35(1):83-101
references: 22057897
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: J Mol Cell Biol. 2011 Oct;3(5):276-82
references: 21669942
references: Nat Genet. 1993 Nov;5(3):230-5
references: 8275086
references: Aging Cell. 2011 Oct;10(5):832-43
references: 21624038
references: J Neurosci. 2006 Feb 22;26(8):2290-9
references: 16495456
references: Oncogene. 2008 Apr 7;27(16):2312-9
references: 18391973
references: Science. 2004 Jul 16;305(5682):390-2
references: 15205477
references: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8538-42
references: 8378328
references: J Cell Biol. 2003 Aug 18;162(4):613-22
references: 12913110
references: Science. 2002 Jul 19;297(5580):353-6
references: 12130773
references: Blood. 1997 Nov 1;90(9):3714-9
references: 9345057
references: Cell Death Differ. 2005 Aug;12(8):1015-20
references: 15933736
references: Channels (Austin). 2009 Jul-Aug;3(4):233-8
references: 19690465
references: Mol Biol Cell. 2009 Mar;20(5):1533-44
references: 19144826
references: EMBO J. 1998 Apr 15;17(8):2224-34
references: 9545236
references: J Neurosci. 2000 Feb 15;20(4):1386-92
references: 10662829
references: J Cell Biol. 2005 Apr 25;169(2):331-9
references: 15837797
references: Cell Cycle. 2005 Jul;4(7):908-13
references: 15917664
references: Neuropharmacology. 2010 Sep-Oct;59(4-5):358-65
references: 20420844
references: Nat Rev Mol Cell Biol. 2007 Jun;8(6):440-50
references: 17522590
references: Oncogene. 2005 Nov 14;24(50):7410-25
references: 16288288
references: Oncogene. 2008 Apr 7;27(16):2263-75
references: 18391969
references: Cell Death Differ. 2006 Jan;13(1):75-83
references: 15947787
references: J Neurosci. 2011 Feb 23;31(8):2721-33
references: 21414895
references: J Biol Chem. 2007 Oct 5;282(40):29368-74
references: 17702754
references: Cell. 2012 Mar 16;148(6):1204-22
references: 22424230
references: J Biol Chem. 2009 Apr 24;284(17):11285-92
references: 19221179
references: Cell Death Differ. 2004 Jan;11(1):38-48
references: 14647239
references: J Alzheimers Dis. 2001 Feb;3(1):75-80
references: 12214075
references: Curr Neurovasc Res. 2009 Feb;6(1):70-81
references: 19355928
references: Cell. 2006 Jun 2;125(5):987-1001
references: 16751106
references: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8362-6
references: 1924295
references: J Neurosci. 2007 Jan 24;27(4):893-900
references: 17251431
references: Oncogene. 1997 Jan 16;14(2):195-202
references: 9010221
references: J Biol Chem. 2012 Jan 6;287(2):1545-55
references: 22128155
references: Science. 2002 Mar 29;295(5564):2450-2
references: 11884717
references: Cell Death Dis. 2012 May 17;3:e309
references: 22592316
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11285-90
references: 13679577
references: Genes Chromosomes Cancer. 1994 Oct;11(2):79-84
references: 7529552
references: J Neurosci. 2002 May 1;22(9):3376-85
references: 11978814
references: Mol Cell. 2008 Oct 24;32(2):221-31
references: 18951090
references: J Neurochem. 2005 Nov;95(3):834-47
references: 16135089
references: Cancer Res. 2006 Jan 1;66(1):212-20
references: 16397234
references: Clin Cancer Res. 2009 Feb 1;15(3):752-7
references: 19188143
references: J Biol Chem. 2003 Sep 19;278(38):35959-67
references: 12857750