title: Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene.
abstract: Activation of gene expression by FOXO transcription factors can promote neuronal death in response to loss of trophic support, or oxidative stress. The predominant neuronal FOXOs, FOXO1 and FOXO3, promote the expression of pro-death genes, such as Fas Ligand, Bim and Txnip. Neuroprotective signals initiated by neurotrophins, growth factors or synaptic activity trigger the nuclear export of FOXOs via activation of the PI3K-Akt pathway. One key aspect of FOXO regulation is that once PI3K-Akt activity has returned to baseline, FOXOs return to the nucleus to resume the activation of their target genes. Thus, the FOXO-inhibiting capacity of the PI3K-Akt pathway is thought to be short-lived. However, we show here that synaptic NMDA receptor activity not only triggers FOXO export, but also suppresses the expression of FOXO1. Blockade of PI3K activity prevents both FOXO nuclear export and suppression of FOXO1 expression, raising the possibility that FOXO1 is itself a FOXO target gene. We found that FOXO3, and to a lesser extent FOXO1 transactivates the FOXO1 promoter via a consensus FOXO binding site (GTA AAC AA), and also an upstream sequence resembling a classical FOXO-binding insulin response sequence (CAA AAC AA). Activity-dependent suppression of the FOXO1 promoter is mediated through the proximal GTAAACAA sequence. Similar suppression via this site is observed by activating neuronal IGF-1 receptors by exogenous insulin. Thus, through a feed-forward inhibition mechanism, synaptic activity triggers FOXO export resulting in suppression of FOXO1 expression. These results suggest that FOXO-inactivating signals are likely to result in longer-term inhibition of FOXO target gene expression than previously thought.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Bashayer
authors.initials: B
authors.lastname: Al-Mubarak
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Soriano
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C499515:FOXO3 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
references.citation: J Biol Chem. 2009 Apr 17;284(16):10334-42
references.pmid: 19244250
references.citation: Science. 2004 Mar 26;303(5666):2011-5
references.pmid: 14976264
references.citation: Eur J Hum Genet. 2007 Mar;15(3):294-301
references.pmid: 17245409
references.citation: Neurosci Lett. 2006 May 1;398(1-2):39-43
references.pmid: 16423457
references.citation: Nat Neurosci. 2006 Jul;9(7):901-6
references.pmid: 16783365
references.citation: Ann N Y Acad Sci. 2005 Dec;1055:1-12
references.pmid: 16387713
references.citation: Biochem J. 2000 Jul 15;349(Pt 2):629-34
references.pmid: 10880363
references.citation: Nat Neurosci. 2001 Mar;4(3):261-7
references.pmid: 11224542
references.citation: Cell Death Differ. 2007 Mar;14(3):534-47
references.pmid: 16888645
references.citation: Cell. 2006 Jun 2;125(5):987-1001
references.pmid: 16751106
references.citation: J Biol Chem. 2004 Jul 16;279(29):30369-74
references.pmid: 15128745
references.citation: Channels (Austin). 2009 Jan-Feb;3(1):12-5
references.pmid: 19221512
references.citation: Curr Diab Rep. 2009 Jun;9(3):208-14
references.pmid: 19490822
references.citation: BMC Cell Biol. 2006 Feb 28;7:10
references.pmid: 16507111
references.citation: Trends Mol Med. 2008 May;14(5):219-27
references.pmid: 18403263
references.citation: Cell. 1999 Mar 19;96(6):857-68
references.pmid: 10102273
references.citation: Science. 1993 Apr 9;260(5105):181-6
references.pmid: 8097060
references.citation: Curr Neurovasc Res. 2007 Nov;4(4):295-302
references.pmid: 18045156
references.citation: EMBO J. 2000 Mar 1;19(5):989-96
references.pmid: 10698940
references.citation: J Cell Sci. 2007 Aug 1;120(Pt 15):2479-87
references.pmid: 17646672
references.citation: J Neurosci. 2006 Apr 26;26(17):4509-18
references.pmid: 16641230
references.citation: J Biol Chem. 1999 Jun 11;274(24):17184-92
references.pmid: 10358076
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Nov 15;827(1):65-75
references.pmid: 16183338
references.citation: J Biol Chem. 2009 Apr 24;284(17):11285-92
references.pmid: 19221179
references.citation: J Neurochem. 2006 Jun;97(6):1634-58
references.pmid: 16805774
references.citation: Trends Cell Biol. 2008 Sep;18(9):421-9
references.pmid: 18715783
references.citation: J Clin Invest. 2004 Apr;113(7):1059-68
references.pmid: 15057313
references.citation: J Neurosci. 2005 Apr 27;25(17):4279-87
references.pmid: 15858054
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):936-8
references.pmid: 17052231
references.citation: J Neurochem. 2005 Apr;93(1):171-85
references.pmid: 15773917
references.citation: Nat Neurosci. 2008 Apr;11(4):476-87
references.pmid: 18344994
references.citation: J Neurochem. 2005 Jun;93(5):1209-19
references.pmid: 15934941
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):126-36
references.pmid: 18394876
references.citation: Science. 1991 Aug 23;253(5022):912-4
references.pmid: 1715095