ISSN 1007-7626 CN 11-3870 / Q 2010 3 Chinese Journal of Biochemistry and Molecular Biology 263 203 ~ 208 FoxO1 * 510080 FoxO1 Fox DNA / PI-3K Akt FoxO1 FoxO1 FoxO1 FoxO1 DNA FoxO1 FoxO1 FoxO1 FoxO1 FoxO1 Q291 FoxO1 Transcription Factor and Its Posttranslational Modification ZHONG QianDENG Yu-Bin * Department of PathophysiologyZhongshan Medical School Sun Yat-sen UniversityGuangzhou 510080 China Abstract As a member of the Fox familyfoxo1 transcription factor is involved in the regulation of apoptosisoxidative stressdna damage repaircancer developmentangiogenesis and glucose metabolism The phosphatidylinositol 3-kinase PI3Kin the Akt pathway phosphorylates FoxO1 and mobilizes FoxO1 from the nuclei to the cytoplasm leading to inactivation of FoxO1 and its impact on the downstream targets Acetylation of FoxO1 attenuates its binding to the target DNA and enhances its phosphorylationthereby decreases the transcription activities of FoxO1 This review focuses on the FoxO1 posttranslational modifications and their roles in the transcriptional regulation Key words FoxO1transcription factorphosphorylationacetylation FoxO1 Fox 2 FoxO1 100 forkhead Fox 1 FoxO1 FoxO Fox FoxO1 FoxO3 FoxO4 1 1 FoxO1 FoxO6 FoxO1 655 N DNA / FoxO 2009-07-03 2010-01-21 Akt /PKB FoxO FoxO1 FoxO1 FoxO1 FoxO1 FoxO1 FoxO1 FoxO1 2008-34 2009 * Tel020-88385762E-maildengyub@ mail sysu edu cn ReceivedJuly 32009AcceptedJunary 21 2010 Supported by National university student innovation test plansun Yat-sen University 2008-34 Yat-sen Innovative Training Program of Sun Yatsen University 2009 * Corresponding author Tel020-88385762 FoxO1 1 FoxOs E-maildengyub@ mail sysu edu cn
204 26 forkhead FK DNA C / transactivation domainad FoxO1 transrepression domainrd Nuclear Localization SignalNLS Nuclear Export SequenceNES 3 SH3 RD FoxO1 Fig 1 4 Fig 1 The diagram of FoxO1 protein 655 amino acid 4 FoxO1 consists of an N-terminal domain containing a repression domain region RDand a forkhead-domain FKand a C-terminal domain containing a transactivation domain TA FoxO1 contains a nuclear location signal NLSand a nuclear export signal NES The residues that undergo phophorylation by Akt are labeled with P the lysine residues which can be acetylated are labeled with A 1 2 FoxO1 FoxO1 1 2 1 FoxO1 2Ang-2 8 9 Ang-2 Ang-1 FoxO1 FoxO1 Ang-2 9 5 Akt /FoxO1 8 11-37 -40 ephrin -B2 FoxO1-1 -2 FoxO1 5 FoxO1 1 2 2 FoxOs 3 FoxO FoxO1 FoxO3 5 FoxO1 FoxO4-37 -40 10 FoxO3-37 / -40-11 6 FoxO1 FoxO3 FoxO4 FoxO1 / + ephrin -B2 65% FoxO3 / FoxO4 / CD4 + CD8 + ephrin -B2 E11 5 Ephrin -B2 FoxO1 12 FoxOs 7 FoxO1 FoxOs 2 FoxOs -1 angiopoietin-1ang-1 FoxOs Ang-1 Akt FoxO1 FoxO1 13
3 FoxO1 205 1 3 FoxO1 1 3 1 FoxO1 PAX FoxO1 FKHR forkhead in rhabdomyosarcomas FoxO1 21 1 FoxO1 FoxO1 FoxO1 22 t213 2 1 FoxO1 β t113fkhr PAX3 2 β PAX7 FKHR 14 15 PAX3-FKHR PAX7-1 3 2 PAX3-FKHR β PAX3-FKHR 1 55% ~ 75% PAX3-FKHR β PAX3 DNA forkhead DNA FKHR 16 23 24 PAX3 -FKHR JNK Akt PAX3 FKHR FoxO1 Myf6 pancreatic transcription factor Pdx-1 24 FKHR Pdx 1 β β PAX3-FKHR Ink4a /ARF Trp53 Trp53 Ink4a /ARF β β / PAX3 - FKHR G 1 β ΒIRKO PAX3 - FKHR FoxO1 FoxO1 Pdx-1 PAX3 - FKHR /FoxO1 /Pdx-1 β 2 FoxO1 2 2 FoxO1 FoxO1 PPARγ FoxO1 Thr24 Ser246 Ser256 Ser284 Ser295 Ser319 Ser326 Ser413 Ser415 Ser429 Ser467 Ser475 Thr557 GLUT4 FoxO1 PPARγ PPARγ Asada FoxO1 GLUT4 FoxO1 Ser246 Ser413 Ser415 Ser429 Ser467 FoxO1 PPARγ Ser475 Thr557 1α Pgc1α G6Pase PEPCK FoxO1 Daf-16 /IGF-1 1 / 19 /IGF-1 PI-3K -3 4- Akt FoxO1 Thr24 Ser256 Ser319 20 Fig 1 FoxO1 14-3-3 FoxO1 β β Glut2 FoxO1 3
206 26 FoxO1 FoxO1 DNA FoxO1 FoxO1 FoxO1 DNA 30 FoxO1 35 36 2 3 FoxO1 3 1 FoxO1 Akt / PKB FoxO1 Ser256 3 FoxOs FoxOs FoxO1 Akt FoxO1 FoxO1 p15ink4bp19ink4d FoxO1 Ser256 p15ink4bp19ink4d FoxO1 CDKI 36 CDK4 CDK Sirt2 3 NAD 31 p27 KIP1 CDK2 FoxO1 p27 KIP1 FoxO1 AKT- Sirt2 Sirt2 CDK2- FoxO1 Sirt2 FoxO1 1 FoxO1 Ser256 FoxO1 FoxO1 PPARγ FoxO1 PPARγ DNA CDK2 CDK2 37 DNA DNA 3 2 FoxO1 CDK2 Sirt1 FoxO1 FoxO1 Ser249 FoxO1 CDK2 1 LXXLL FoxO1 FoxO1 FoxO1 FoxO 3A / PTEN FoxO1 32 LXXAA 3 Akt DNA CDK2 FoxO1 FoxO1 CDK2 IGFBP-1 G6Pase FoxO1 DNA LXXLL FoxO1 Sirt1 33 FoxO1 CDK1 3A /LXXAA FoxO1 Lepr db / db CDK1 FoxO1 Ser249 FoxO1 14-3-3 FoxO1 Sirt1 FoxO1 34 Huang 32 33 Sirt1 CDK2 38 CDK FoxO1 3 FoxO1 3T3 -L1 Sirt1 LXXLL G6Pase IGFBP -1 FoxO1 FoxO1 FoxO1 FoxO1 3 Lys242 Lys245 Lys262 CBP FoxO1 Sirt1 Sirt2
3 FoxO1 207 References 1 Huang HTindall DJ Dynamic FoxO transcription factors J J Cell Sci2007120152479-2487 2 Arden KC FoxOs in tumor suppression and stem cell maintenance J Cell 2007 128 2 235-237 3 Obsil TObsilova V Structure /function relationships underlying regulation of FOXO transcription factors J Oncogene 2008 27 162263-2275 4 Zhao HHHerrera RECoronado-Heinsohn Eet al Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions J J Biol Chem2001 27630 27907-27912 5 Furuyama TKitayama KShimoda Yet al Abnormal angiogenesis in Foxo1 Fkhr-deficient mice J J Biol Chem 20042793334741-34749 6 Simon AMMcWhorter AR Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40 J Dev Biol2002 2512 206-220 7 Gerety SSAnderson DJ Cardiovascular ephrinb2 function is essential for embryonic angiogenesis J Development2002 1296 1397-1410 8 Daly CWong VBurova Eet al Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR FOXO1 J Genes Dev2004 18 9 1060-1071 9 Potente MUrbich CSasaki Ket al Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization J J Clin Invest2005 1159 2382-2392 10Furuyama TNakazawa TNakano Iet al Identification of the differential distribution patterns of mrnas and consensus binding sequences for mouse DAF-16 homologues J Biochem J2000 3492 629-634 11Castrillon DHMiao LKollipara Ret al Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a J Science20033015630215-218 12Paik JHKollipara RChu G et al FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis J Cell2007 1282 309-323 13Tothova ZKollipara RHuntly BJet al FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress J Cell 2007 1282 325-339 14Kikuchi KTsuchiya KOtabe Oet al Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma J Biochem Biophys Res Commun20083653 568-574 15Sorensen PHLynch JCQualman SJet al PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcomaa report from the children s oncology group J J Clin Oncol200220112672-2679 16Galili NDavis RJFredericks WJet al Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma J Nat Genet1993 53 230-235 17Keller CArenkiel BRCoffin CMet al Alveolar rhabdomyosarcomas in conditional Pax3Fkhr micecooperativity of Ink4a / ARF and Trp53 loss of function J Genes Dev 2004 18212614-2626 18Asada SDaitoku HMatsuzaki H et al Mitogen-activated protein kinaseserk and p38phosphorylate and regulate Foxo1 J Cell Signal2007 193 519-527 19Gottlieb SRuvkun G daf-2daf-16 and daf-23genetically interacting genes controlling Dauer formation in Caenorhabditis elegans J Genetics19941371 107-120 20Tang EDNuez GBarr FGet al Negative regulation of the forkhead transcription factor FKHR by Akt J J Biol Chem 19992742416741-16746 21Rena GPrescott ARGuo Set al Roles of the forkhead in rhabdomyosarcoma FKHRphosphorylation sites in regulating 14-3-3 bindingtransactivation and nuclear targetting J Biochem J2001 3543 605-612 22Matsuzaki HDaitoku HHatta Met al Insulin-induced phosphorylation of FKHR Foxo1 targets to proteasomal degradation J Proc Natl Acad Sci U S A2003 100 20 11285-11290 23Ferrannini E Insulin resistance versus insulin deficiency in noninsulin-dependent diabetes mellitus problems and prospects J Endocr Rev1998194 477-490 24Kawamori DKaneto HNakatani Yet al The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation J J Biol Chem20062812 1091-1098 25Bouwens LRooman I Regulation of pancreatic beta-cell mass J Physiol Rev2005854 1255-1270 26Okada TLiew CWHu Jet al Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance J Proc Natl Acad Sci U S A 2007 104 21 8977-8982 27Nakae JKitamura TKitamura Yet al The forkhead transcription factor Foxo1 regulates adipocyte differentiation J Dev Cell200341 119-129 28Armoni MHarel CKarni Set al FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes A novel paradigm to increase insulin sensitivity J J Biol Chem200628129 19881-19891 29Puigserver PRhee JDonovan J et al Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction J Nature20034236939550-555 30Matsumoto MHan SKitamura T et al Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism J J Clin Invest 2006 11692464-2472 31Katayama KNakamura ASugimoto Yet al FOXO transcription factor-dependent p15 INK4band p19 INK4d expression J Oncogene200827121677-1686
208 26 32Huang HRegan KMLou Zet al CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage J Science20063145797294-297 33Huang HTindall DJ CDK2 and FOXO1a fork in the road for cell fate decisions J Cell Cycle2007 68 902-906 34Yuan ZBecker EBMerlo P et al Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons J Science 200831958701665-1668 35Daitoku HHatta MMatsuzaki Het al Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity J Proc Natl Acad Sci U S A2004 101 2710042-10047 36Matsuzaki HDaitoku HHatta Met al Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation J Proc Natl Acad Sci U S A2005 1023211278-11283 37Jing EGesta SKahn CR SIRT2 regulates adipocyte differentiation through FoxO1 acetylation /deacetylation J Cell Metab200762 105-114 38Nakae JCao YDaitoku Het al The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity J J Clin Invest2006 116 9 2473-2483 202 2010 10 8 13-15 300 021-54921090 11 8 18-20 150 021-54921090 12 500 8 23-26 021-54921088 021-54921090 13 8 23-26 50 010-66939433 14 DNA 40 8 27-29 021-54921090 15 RNA 200 9 020-84039682 16 9 15-16 200 010-80705188 10 17 50 010-66939433 18 10 120 010-82109695