The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.

FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO factors is a shuttling system, which confines FoxO factors to either the nucleus or the cytosol. Shuttling of FoxO requires protein phosphorylation within several domains, and association with 14-3-3 proteins and the nuclear transport machinery. Description of the FoxO-shuttling mechanism contributes to the understanding of FoxO function in relation to signalling and gene regulation.

[1]  M. Waterfield,et al.  Signaling by distinct classes of phosphoinositide 3-kinases. , 1999, Experimental cell research.

[2]  D R Alessi,et al.  PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? , 2001, Journal of cell science.

[3]  P. Graves,et al.  Role of COOH-terminal Phosphorylation in the Regulation of Casein Kinase Iδ (*) , 1995, The Journal of Biological Chemistry.

[4]  Michael B. Yaffe,et al.  14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport , 2002, The Journal of cell biology.

[5]  F. Barr,et al.  The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3 , 1995, Molecular and cellular biology.

[6]  M. Fukuoka,et al.  Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. , 2003, International journal of molecular medicine.

[7]  J. Woodgett,et al.  Unravelling the activation mechanisms of protein kinase B/Akt , 2003, FEBS letters.

[8]  T. Laessig,et al.  Insulin-Like Growth Factor-I Blocks Bcl-2 Interacting Mediator of Cell Death (Bim) Induction and Intrinsic Death Signaling in Cerebellar Granule Neurons , 2002, The Journal of Neuroscience.

[9]  A. C. Maiyar,et al.  Expression of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, Is a Cell Survival Response to Multiple Types of Environmental Stress Stimuli in Mammary Epithelial Cells* , 2003, The Journal of Biological Chemistry.

[10]  M. Imae,et al.  Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. , 2003, Journal of molecular endocrinology.

[11]  A. Fukamizu,et al.  Hepatocyte Nuclear Factor-4 Is a Novel Downstream Target of Insulin via FKHR as a Signal-regulated Transcriptional Inhibitor* , 2003, The Journal of Biological Chemistry.

[12]  P. Cohen,et al.  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* , 1999, The Journal of Biological Chemistry.

[13]  W. Biggs,et al.  Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Furuyama,et al.  Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. , 2003, The Biochemical journal.

[15]  Jiandie D. Lin,et al.  PGC-1β in the Regulation of Hepatic Glucose and Energy Metabolism* , 2003, Journal of Biological Chemistry.

[16]  Miki Suzuki,et al.  A forkhead transcription factor FKHR up‐regulates lipoprotein lipase expression in skeletal muscle , 2003, FEBS letters.

[17]  P. Auberger,et al.  Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases , 2003, Oncogene.

[18]  H. Lodish,et al.  Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Greengard,et al.  Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Barr,et al.  The PAX 3-FKHR Fusion Protein Created by the t ( 2 ; 13 ) Translocation in Alveolar Rhabdomyosarcomas Is a More Potent Transcriptional Activator than PAX 3 , 1995 .

[21]  I. Macara,et al.  Inhibition of Nuclear Import by Protein Kinase B (Akt) Regulates the Subcellular Distribution and Activity of the Forkhead Transcription Factor AFX , 2001, Molecular and Cellular Biology.

[22]  J. Kramer,et al.  Expression of Drosophila FOXO regulates growth and can phenocopy starvation , 2003, BMC Developmental Biology.

[23]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.

[24]  K. Abromeit Music Received , 2023, Notes.

[25]  J. Lammers,et al.  Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1 , 2000, Molecular and Cellular Biology.

[26]  P. Cohen,et al.  Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion , 2002, The EMBO journal.

[27]  P. Heinrich,et al.  Akt Modulates STAT3-mediated Gene Expression through a FKHR (FOXO1a)-dependent Mechanism* , 2003, The Journal of Biological Chemistry.

[28]  Hitomi Matsuzaki,et al.  Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[30]  S. R. Datta,et al.  Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway , 2001, Current Opinion in Neurobiology.

[31]  D. Virshup,et al.  Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis. , 1998, The Journal of biological chemistry.

[32]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[33]  C. Martínez-A,et al.  Forkhead transcription factors contribute to execution of the mitotic programme in mammals , 2001, Nature.

[34]  Geert J. P. L. Kops,et al.  The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-21 , 2002, The Journal of Immunology.

[35]  J. Bos,et al.  Regulation of the Forkhead Transcription Factor AFX by Ral-Dependent Phosphorylation of Threonines 447 and 451 , 2001, Molecular and Cellular Biology.

[36]  P. Cohen,et al.  The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. , 2001, The Biochemical journal.

[37]  D. E. Anderson,et al.  Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. , 2003, Biochemistry.

[38]  C. Sunkel,et al.  The casein kinase 1 alpha gene of Drosophila melanogaster is developmentally regulated and the kinase activity of the protein induced by DNA damage. , 1996, Journal of cell science.

[39]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[40]  R. Coombes,et al.  FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines* , 2003, Journal of Biological Chemistry.

[41]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[42]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[43]  L. Platanias,et al.  Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells , 2002, Oncogene.

[44]  C. Osborne,et al.  Forkhead Homologue in Rhabdomyosarcoma Functions as a Bifunctional Nuclear Receptor-interacting Protein with Both Coactivator and Corepressor Functions* , 2001, The Journal of Biological Chemistry.

[45]  Geert J. P. L. Kops,et al.  Direct control of the Forkhead transcription factor AFX by protein kinase B , 1999, Nature.

[46]  A. Tobin,et al.  Phosphorylation and Regulation of a Gq/11-coupled Receptor by Casein Kinase 1α* , 2000, The Journal of Biological Chemistry.

[47]  A. Barthel,et al.  DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. , 2003, Biochemical and biophysical research communications.

[48]  L. Larose,et al.  A Casein Kinase I Activity Is Constitutively Associated with Nck* , 1997, The Journal of Biological Chemistry.

[49]  D. Accili,et al.  Differential regulation of gene expression by insulin and IGF‐1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR , 2000, The EMBO journal.

[50]  E. Hafen,et al.  The Drosophila Forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling , 2003, Journal of biology.

[51]  G. Ruvkun,et al.  DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[52]  W. Gu,et al.  Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[53]  P. Coffer,et al.  FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons , 2003, The Journal of cell biology.

[54]  M. Lane,et al.  Convergence of Peroxisome Proliferator-activated Receptor γ and Foxo1 Signaling Pathways* , 2003, Journal of Biological Chemistry.

[55]  P. Wijchers,et al.  FoxO6, a Novel Member of the FoxO Class of Transcription Factors with Distinct Shuttling Dynamics* , 2003, Journal of Biological Chemistry.

[56]  Brian A. Hemmings,et al.  Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a) , 2001, Molecular and Cellular Biology.

[57]  P. Graves,et al.  Phosphate groups as substrate determinants for casein kinase I action. , 1990, The Journal of biological chemistry.

[58]  R. Tjian,et al.  Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. , 2003, Genes & development.

[59]  P. Cohen,et al.  Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase‐1 and p70 S6 kinase , 1996, FEBS letters.

[60]  J. Biegel,et al.  Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. , 1995, Human molecular genetics.

[61]  Michael Majeski,et al.  Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms. , 2004, The Biochemical journal.

[62]  J. Arthur,et al.  In vivo role of the PIF‐binding docking site of PDK1 defined by knock‐in mutation , 2003, The EMBO journal.

[63]  J. Lammers,et al.  Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 , 2000, Current Biology.

[64]  H. Joost,et al.  Sequence Characteristics, Subcellular Localization, and Substrate Specificity of DYRK-related Kinases, a Novel Family of Dual Specificity Protein Kinases* , 1998, The Journal of Biological Chemistry.

[65]  E. O’Shea,et al.  New perspectives on nuclear transport. , 2001, Annual review of genetics.

[66]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[67]  A. Carrera,et al.  Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead , 2004, Molecular and Cellular Biology.

[68]  Joseph Avruch,et al.  A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity , 1998, Nature.

[69]  L. Khachigian,et al.  Signaling and transcriptional control of Fas ligand gene expression , 2003, Cell Death and Differentiation.

[70]  D. Alessi Discovery of PDK1, one of the missing links in insulin signal transduction. Colworth Medal Lecture. , 2001, Biochemical Society transactions.

[71]  B. Pyrzyńska,et al.  Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells , 2003, Oncogene.

[72]  D. Yee,et al.  FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. , 1999, Endocrinology.

[73]  R. Medema,et al.  AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 , 2000, Nature.

[74]  H. Taylor,et al.  Regulation of Insulin-Like Growth Factor Binding Protein-1 Promoter Activity by FKHR and HOXA10 in Primate Endometrial Cells1 , 2003, Biology of reproduction.

[75]  P. Cohen,et al.  D4476, a cell‐permeant inhibitor of CK1, suppresses the site‐specific phosphorylation and nuclear exclusion of FOXO1a , 2004, EMBO reports.

[76]  M. Dasso The Ran GTPase: Theme and Variations , 2002, Current Biology.

[77]  W. Cavenee,et al.  Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse , 2001 .

[78]  Hui Li,et al.  Differential Mechanisms of Nuclear Receptor Regulation by Receptor-associated Coactivator 3* , 2000, The Journal of Biological Chemistry.

[79]  E. Nagoshi,et al.  Nucleocytoplasmic protein transport and recycling of Ran. , 1999, Cell structure and function.

[80]  X. Estivill,et al.  Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice , 2002, Molecular and Cellular Biology.

[81]  B. Vanhaesebroeck,et al.  The PI3K-PDK1 connection: more than just a road to PKB. , 2000, The Biochemical journal.

[82]  P. Cohen,et al.  Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. , 2001, The Biochemical journal.

[83]  D. Tindall,et al.  Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells* , 2004, Journal of Biological Chemistry.

[84]  W. Tsai,et al.  Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion. , 2003, Endocrinology.

[85]  M Heisenberg,et al.  minibrain: A new protein kinase family involved in postembryonic neurogenesis in Drosophila , 1995, Neuron.

[86]  W. Sellers,et al.  A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. , 2002, Cancer cell.

[87]  A. Schürmann,et al.  Dyrk, a Dual Specificity Protein Kinase with Unique Structural Features Whose Activity Is Dependent on Tyrosine Residues between Subdomains VII and VIII (*) , 1996, The Journal of Biological Chemistry.

[88]  R. Weigel,et al.  Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family* , 2001, The Journal of Biological Chemistry.

[89]  T. Blundell,et al.  Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. , 2001, The Biochemical journal.

[90]  D. Accili,et al.  Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 , 2002, Nature Genetics.

[91]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[92]  Rakesh Nagarajan,et al.  FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression , 2002, The Journal of Biological Chemistry.

[93]  D. Accili,et al.  Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. , 2003, American journal of physiology. Endocrinology and metabolism.

[94]  L. Guarente,et al.  Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans , 2001, Nature.

[95]  T. Johnson,et al.  daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans , 2001, Current Biology.

[96]  Michael B Yaffe,et al.  How do 14‐3‐3 proteins work? – Gatekeeper phosphorylation and the molecular anvil hypothesis , 2002, FEBS letters.

[97]  R. O’Brien,et al.  Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. , 1999, Diabetes.

[98]  A. Tobin,et al.  Stimulus-dependent Phosphorylation of G-protein-coupled Receptors by Casein Kinase 1α* , 1997, The Journal of Biological Chemistry.

[99]  D. Pearce The role of SGK1 in hormone-regulated sodium transport , 2001, Trends in Endocrinology & Metabolism.

[100]  D. Accili,et al.  The forkhead transcription factor Foxo1 regulates adipocyte differentiation. , 2003, Developmental cell.

[101]  M. Rechler,et al.  Characterization of Insulin Inhibition of Transactivation by a C-terminal Fragment of the Forkhead Transcription Factor Foxo1 in Rat Hepatoma Cells* , 2003, Journal of Biological Chemistry.

[102]  G M Cohen,et al.  Caspases: the executioners of apoptosis. , 1997, The Biochemical journal.

[103]  Raymond Y. N. Lee,et al.  Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway , 2001, Current Biology.

[104]  C. Rochette-Egly Nuclear receptors: integration of multiple signalling pathways through phosphorylation. , 2003, Cellular signalling.

[105]  Sung-jin Kim,et al.  Nuclear matrix association of insulin receptor and IRS-1 by insulin in osteoblast-like UMR-106 cells. , 2003, Biochemical and biophysical research communications.

[106]  N. L. La Thangue,et al.  p300/CBP proteins: HATs for transcriptional bridges and scaffolds. , 2001, Journal of cell science.

[107]  Y. Kido,et al.  The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. , 2002, The Journal of clinical investigation.

[108]  Stephen Adam,et al.  Phosphorylation of Serine 256 Suppresses Transactivation by FKHR (FOXO1) by Multiple Mechanisms , 2002, The Journal of Biological Chemistry.

[109]  C. Thompson,et al.  Akt Activation Promotes Degradation of Tuberin and FOXO3a via the Proteasome* , 2003, The Journal of Biological Chemistry.

[110]  E. Nagata,et al.  PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis , 2003, Nature Neuroscience.

[111]  J. Brosens,et al.  Cyclic AMP-induced Forkhead Transcription Factor, FKHR, Cooperates with CCAAT/Enhancer-binding Protein β in Differentiating Human Endometrial Stromal Cells* , 2002, The Journal of Biological Chemistry.

[112]  J. Bos All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral , 1998, The EMBO journal.

[113]  M. J. Fry,et al.  The phosphoinositide (PI) 3-kinase family , 2003, Journal of Cell Science.

[114]  G. Ruvkun,et al.  Phosphatidylinositol 3-Kinase Signaling Inhibits DAF-16 DNA Binding and Function via 14-3-3-dependent and 14-3-3-independent Pathways* , 2001, The Journal of Biological Chemistry.

[115]  S. Kuersten,et al.  Nucleocytoplasmic transport: Ran, beta and beyond. , 2001, Trends in cell biology.

[116]  G. Jenster,et al.  AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR , 2003, Molecular and Cellular Biology.

[117]  Luquan Wang,et al.  Transforming Growth Factor-β2 Is a Transcriptional Target for Akt/Protein Kinase B via Forkhead Transcription Factor* , 2002, The Journal of Biological Chemistry.

[118]  J. Bos,et al.  Involvement of p21ras in activation of extracellular signal-regulated kinase 2 , 1992, Nature.

[119]  S. D. Gross,et al.  Casein kinase I: spatial organization and positioning of a multifunctional protein kinase family. , 1998, Cellular signalling.