Original Article| Volume 62, ISSUE 12, P1423-1430, December 15, 2007

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Lithium Reduces FoxO3a Transcriptional Activity by Decreasing Its Intracellular Content

  • Zhengquan Mao
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
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  • Liqin Liu
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
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  • Rusheng Zhang
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
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  • Xiaohua Li
    Address reprint rquests to Xiaohua Li, M.D., Ph.D., Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1075 Sparks Center, 1720 7th Avenue South, Birmingham, AL 35294-0017
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
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      Forkhead box, class O (FoxO) transcription factors play important roles in cell fate, differentiation, survival, and stress regulation. A subtype of mammalian FoxO transcription factors, FoxO3a, is widely distributed in the brain, and its activity is regulated by neurotrophins, such as brain-derived neurotrophic factor (BDNF), resulting in transcriptional inactivation of FoxO3a. Searching for therapeutic targets downstream of BDNF signaling will facilitate the development of new treatment approaches for mood disorders.


      Transcriptional activity, target gene expression, and protein levels of FoxO3a were measured in cultured cells and mouse brain after lithium treatment.


      Lithium significantly reduced FoxO3a transcriptional activity and gene expression. The effect of lithium may be the result of a significant reduction of the FoxO3a protein levels in both the cytosol and nucleus that was mediated by an Akt-independent action. More importantly, this effect of lithium was observed in cells and mouse brain after therapeutically relevant lithium treatments.


      Lithium, an established treatment for mood disorders, has a prominent effect on FoxO3a transcriptional activity and the effect is likely therapeutically relevant. These results warrant further study to identify if FoxO3a is a transcriptional target in the neuropathology and treatment of mood disorders.

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        • Greer E.L.
        • Brunet A.
        FOXO transcription factors at the interface between longevity and tumor suppression.
        Oncogene. 2005; 24: 7410-7425
        • Burgering B.M.
        • Medema R.H.
        Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty.
        J Leukoc Biol. 2003; 73: 689-701
        • Furuyama T.
        • Nakazawa T.
        • Nakano I.
        • Mori N.
        Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues.
        Biochem J. 2000; 349: 629-634
        • Hoekman M.F.
        • Jacobs F.M.
        • Smidt M.P.
        • Burbach J.P.
        Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain.
        Gene Expr Patterns. 2006; 6: 134-140
        • Brunet A.
        • Bonni A.
        • Zigmond M.J.
        • Lin M.Z.
        • Juo P.
        • Hu L.S.
        • et al.
        Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
        Cell. 1999; 96: 857-868
        • Nakae J.
        • Park B.C.
        • Accili D.
        Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway.
        J Biol Chem. 1999; 274: 15982-15985
        • Tang E.D.
        • Nunez G.
        • Barr F.G.
        • Guan K.L.
        Negative regulation of the forkhead transcription factor FKHR by Akt.
        J Biol Chem. 1999; 274: 16741-16746
        • Rena G.
        • Guo S.
        • Cichy S.C.
        • Unterman T.G.
        • Cohen P.
        Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.
        J Biol Chem. 1999; 274: 17179-17183
        • Takaishi H.
        • Konishi H.
        • Matsuzaki H.
        • Ono Y.
        • Shirai Y.
        • Saito N.
        • et al.
        Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B.
        Proc Natl Acad Sci U S A. 1999; 96: 11836-11841
        • del Peso L.
        • Gonzalez V.M.
        • Hernandez R.
        • Barr F.G.
        • Nunez G.
        Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt.
        Oncogene. 1999; 18: 7328-7333
        • Guo S.
        • Rena G.
        • Cichy S.
        • He X.
        • Cohen P.
        • Unterman T.
        Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence.
        J Biol Chem. 1999; 274: 17184-17192
        • Biggs 3rd, W.H.
        • Meisenhelder J.
        • Hunter T.
        • Cavenee W.K.
        • Arden K.C.
        Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1.
        Proc Natl Acad Sci U S A. 1999; 96: 7421-7426
        • Murphy C.T.
        • McCarroll S.A.
        • Bargmann C.I.
        • Fraser A.
        • Kamath R.S.
        • Ahringer J.
        • et al.
        Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans.
        Nature. 2003; 424: 277-283
        • Kops G.J.
        • Medema R.H.
        • Glassford J.
        • Essers M.A.
        • Dijkers P.F.
        • Coffer P.J.
        • et al.
        Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.
        Mol Cell Biol. 2002; 22: 2025-2036
        • Kops G.J.
        • Dansen T.B.
        • Polderman P.E.
        • Saarloos I.
        • Wirtz K.W.
        • Coffer P.J.
        • et al.
        Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress.
        Nature. 2002; 419: 316-321
        • Tissenbaum H.A.
        • Guarente L.
        Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans.
        Nature. 2001; 410: 227-230
        • Zhu W.
        • Bijur G.N.
        • Styles N.A.
        • Li X.
        Regulation of FOXO3a by brain-derived neurotrophic factor in differentiated human SH-SY5Y neuroblastoma cells.
        Brain Res Mol Brain Res. 2004; 126: 45-56
        • Dijkers P.F.
        • Medema R.H.
        • Lammers J.W.
        • Koenderman L.
        • Coffer P.J.
        Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1.
        Curr Biol. 2000; 10: 1201-1204
        • Stahl M.
        • Dijkers P.F.
        • Kops G.J.
        • Lens S.M.
        • Coffer P.J.
        • Burgering B.M.
        • et al.
        The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2.
        J Immunol. 2002; 168: 5024-5031
        • Mai L.
        • Jope R.S.
        • Li X.
        BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents.
        J Neurochem. 2002; 82: 75-83
        • Zheng W.H.
        • Kar S.
        • Quirion R.
        Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells.
        J Biol Chem. 2000; 275: 39152-39158
        • Zheng W.H.
        • Kar S.
        • Quirion R.
        FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling.
        J Neurochem. 2002; 80: 1049-1061
        • Duman R.S.
        Synaptic plasticity and mood disorders.
        Mol Psychiatry. 2002; 7: S29-S34
        • Neves-Pereira M.
        • Mundo E.
        • Muglia P.
        • King N.
        • Macciardi F.
        • Kennedy J.L.
        The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: Evidence from a family-based association study.
        Am J Hum Genet. 2002; 71: 651-655
        • Berton O.
        • Nestler E.J.
        New approaches to antidepressant drug discovery: Beyond monoamines.
        Nat Rev Neurosci. 2006; 7: 137-151
        • Zheng W.H.
        • Kar S.
        • Quirion R.
        Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons.
        Mol Pharmacol. 2002; 62: 225-233
        • Shang Y.
        • Hu X.
        • DiRenzo J.
        • Lazar M.A.
        • Brown M.
        Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription.
        Cell. 2000; 103: 843-852
        • Li X.
        • Rosborough K.
        • Friedman A.B.
        • Zhu W.
        • Roth K.A.
        Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics.
        Int J Neuropsychopharmacol. 2007; 10: 7-19
        • Matsui H.
        • Shinjyo T.
        • Inaba T.
        Structure of the human Bim gene and its transcriptional regulation in Baf-3, interleukin-3-dependent hematopoietic cells.
        Mol Biol Rep. 2005; 32: 79-85
        • Gilley J.
        • Coffer P.J.
        • Ham J.
        FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.
        J Cell Biol. 2003; 162: 613-622
        • Styles N.A.
        • Zhu W.
        • Li X.
        Phosphorylation and down-regulation of Bim by muscarinic cholinergic receptor activation via protein kinase C.
        Neurochem Int. 2005; 47: 519-527
        • De Sarno P.
        • Li X.
        • Jope R.S.
        Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium.
        Neuropharmacology. 2002; 43: 1158-1164
        • Essers M.A.
        • de Vries-Smits L.M.
        • Barker N.
        • Polderman P.E.
        • Burgering B.M.
        • Korswagen H.C.
        Functional interaction between beta-catenin and FOXO in oxidative stress signaling.
        Science. 2005; 308: 1181-1184
        • G-Amlak M.
        • Uddin S.
        • Mahmud D.
        • Damacela I.
        • Lavelle D.
        • Ahmed M.
        • et al.
        Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway.
        Biochem Biophys Res Commun. 2002; 297: 760-764
        • Duman R.S.
        • Monteggia L.M.
        A neurotrophic model for stress-related mood disorders.
        Biol Psychiatry. 2006; 59: 1116-1127