{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:43:41Z","timestamp":1791146621257,"version":"4.1.0"},"reference-count":48,"publisher":"The Endocrine Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,3,1]]},"abstract":"<jats:p>The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream target of phosphatidylinositol 3-kinase\/Akt signaling, has been reported to suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 regulates myogenesis is not fully understood. We have previously demonstrated that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the autocrine production of IGF-II and the subsequent phosphatidylinositol 3-kinase\/Akt signaling downstream of IGF-II in myogenesis. Here we report a regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation at an early stage and meanwhile leads to proteasome-dependent degradation of a specific subset of components in the mTOR signaling network, including mTOR, raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of FoxO1 requires new protein synthesis, consistent with the idea that a transcriptional target of FoxO1 may be responsible for the degradation of mTOR. We further show that active FoxO1 inhibits IGF-II expression at the transcriptional activation level, through the modulation of mTOR protein levels. Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is a major mediator of FoxO\u2019s inhibitory function in skeletal myogenesis.<\/jats:p>","DOI":"10.1210\/en.2007-1470","type":"journal-article","created":{"date-parts":[[2007,12,14]],"date-time":"2007-12-14T01:45:14Z","timestamp":1197596714000},"page":"1407-1414","source":"Crossref","is-referenced-by-count":56,"title":["Forkhead Box Protein O1 Negatively Regulates Skeletal Myocyte Differentiation through Degradation of Mammalian Target of Rapamycin Pathway Components"],"prefix":"10.1210","volume":"149","author":[{"given":"Ai-Luen","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology (A.-L.W., J.-H.K., C.Z., J.C.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Ho","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology (A.-L.W., J.-H.K., C.Z., J.C.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongben","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology (A.-L.W., J.-H.K., C.Z., J.C.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry G.","family":"Unterman","sequence":"first","affiliation":[{"name":"Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois at Chicago, College of Medicine and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology (A.-L.W., J.-H.K., C.Z., J.C.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2007,12,13]]},"reference":[{"key":"2020071612322083600_R1","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/0092-8674(93)90610-3","article-title":"The MyoD family and myogenesis: redundancy, networks, and thresholds.","volume":"75","author":"Weintraub","year":"1993","journal-title":"Cell"},{"key":"2020071612322083600_R2","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0955-0674(99)00036-8","article-title":"MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation.","volume":"11","author":"Naya","year":"1999","journal-title":"Curr Opin Cell Biol"},{"key":"2020071612322083600_R3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1146\/annurev.ph.53.030191.001221","article-title":"Hormones, growth factors, and myogenic differentiation.","volume":"53","author":"Florini","year":"1991","journal-title":"Annu Rev Physiol"},{"key":"2020071612322083600_R4","doi-asserted-by":"crossref","first-page":"15603","DOI":"10.1073\/pnas.95.26.15603","article-title":"Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function.","volume":"95","author":"Barton-Davis","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612322083600_R5","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/84839","article-title":"Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.","volume":"27","author":"Musaro","year":"2001","journal-title":"Nat Genet"},{"key":"2020071612322083600_R6","doi-asserted-by":"crossref","first-page":"13810","DOI":"10.1016\/S0021-9258(18)80073-4","article-title":"Insulin-like growth factors (IGF) in muscle development. Expression of IGF-I, the IGF-I receptor, and an IGF binding protein during myoblast differentiation.","volume":"264","author":"Tollefsen","year":"1989","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R7","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1073\/pnas.86.5.1543","article-title":"Coordinate expression of insulin-like growth factor II and its receptor during muscle differentiation.","volume":"86","author":"Tollefsen","year":"1989","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612322083600_R8","doi-asserted-by":"crossref","first-page":"15917","DOI":"10.1016\/S0021-9258(18)98496-6","article-title":"\u201cSpontaneous\u201d differentiation of skeletal myoblasts is dependent upon autocrine secretion of insulin-like growth factor-II.","volume":"266","author":"Florini","year":"1991","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R9","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1128\/MCB.19.4.3115","article-title":"Maturation of the myogenic program is induced by postmitotic expression of insulin-like growth factor I.","volume":"19","author":"Musaro","year":"1999","journal-title":"Mol Cell Biol"},{"key":"2020071612322083600_R10","doi-asserted-by":"crossref","first-page":"19146","DOI":"10.1074\/jbc.271.32.19146","article-title":"Phosphatidylinositol 3-kinase inhibitors block differentiation of skeletal muscle cells.","volume":"271","author":"Kaliman","year":"1996","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R11","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1210\/mend.12.1.0047","article-title":"Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells.","volume":"12","author":"Kaliman","year":"1998","journal-title":"Mol Endocrinol"},{"key":"2020071612322083600_R12","doi-asserted-by":"crossref","first-page":"14179","DOI":"10.1073\/pnas.95.24.14179","article-title":"An essential role of phosphatidylinositol 3-kinase in myogenic differentiation.","volume":"95","author":"Jiang","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612322083600_R13","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1073\/pnas.96.5.2077","article-title":"Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt\/protein kinase B.","volume":"96","author":"Jiang","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612322083600_R14","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1083\/jcb.200212107","article-title":"Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors.","volume":"162","author":"Hribal","year":"2003","journal-title":"J Cell Biol"},{"key":"2020071612322083600_R15","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0092-8674(04)00452-0","article-title":"FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.","volume":"117","author":"Accili","year":"2004","journal-title":"Cell"},{"key":"2020071612322083600_R16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.tem.2005.03.010","article-title":"FoxO proteins in insulin action and metabolism.","volume":"16","author":"Barthel","year":"2005","journal-title":"Trends Endocrinol Metab"},{"key":"2020071612322083600_R17","doi-asserted-by":"crossref","first-page":"RE5","DOI":"10.1126\/stke.2003.172.re5","article-title":"The many forks in FOXO\u2019s road","volume":"2003","author":"Tran","year":"2003","journal-title":"Sci STKE"},{"key":"2020071612322083600_R18","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1042\/bj20031450","article-title":"Multiple elements regulate nuclear\/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms.","volume":"378","author":"Zhao","year":"2004","journal-title":"Biochem J"},{"key":"2020071612322083600_R19","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1093\/emboj\/cdg116","article-title":"FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts.","volume":"22","author":"Bois","year":"2003","journal-title":"EMBO J"},{"key":"2020071612322083600_R20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0092-8674(04)00400-3","article-title":"Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.","volume":"117","author":"Sandri","year":"2004","journal-title":"Cell"},{"key":"2020071612322083600_R21","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S1097-2765(04)00211-4","article-title":"The IGF-1\/PI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.","volume":"14","author":"Stitt","year":"2004","journal-title":"Mol Cell"},{"key":"2020071612322083600_R22","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR.","volume":"18","author":"Hay","year":"2004","journal-title":"Genes Dev"},{"key":"2020071612322083600_R23","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.1074\/jbc.274.7.4341","article-title":"Stress-activated protein kinase-2\/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis.","volume":"274","author":"Cuenda","year":"1999","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R24","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/1097-4652(200101)186:1<82::AID-JCP1001>3.0.CO;2-R","article-title":"Insulin produces myogenesis in C2C12 myoblasts by induction of NF-\u03baB and downregulation of AP-1 activities.","volume":"186","author":"Conejo","year":"2001","journal-title":"J Cell Physiol"},{"key":"2020071612322083600_R25","doi-asserted-by":"crossref","first-page":"36079","DOI":"10.1074\/jbc.C100406200","article-title":"The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism.","volume":"276","author":"Erbay","year":"2001","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R26","doi-asserted-by":"crossref","first-page":"16726","DOI":"10.1074\/jbc.M112285200","article-title":"Myogenic differentiation is dependent on both the kinase function and the N-terminal sequence of mammalian target of rapamycin.","volume":"277","author":"Shu","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R27","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1083\/jcb.200307158","article-title":"IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients.","volume":"163","author":"Erbay","year":"2003","journal-title":"J Cell Biol"},{"key":"2020071612322083600_R28","doi-asserted-by":"crossref","first-page":"32009","DOI":"10.1074\/jbc.M506120200","article-title":"Mammalian target of rapamycin (mTOR) signaling is required for a late-stage fusion process during skeletal myotube maturation.","volume":"280","author":"Park","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R29","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex.","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"2020071612322083600_R30","doi-asserted-by":"crossref","first-page":"14222","DOI":"10.1074\/jbc.M413625200","article-title":"FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms.","volume":"280","author":"Bastie","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R31","doi-asserted-by":"crossref","first-page":"3897","DOI":"10.1242\/dev.01255","article-title":"The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span.","volume":"131","author":"Jia","year":"2004","journal-title":"Development"},{"key":"2020071612322083600_R32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0092-8674(02)00808-5","article-title":"mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.","volume":"110","author":"Kim","year":"2002","journal-title":"Cell"},{"key":"2020071612322083600_R33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0092-8674(02)00833-4","article-title":"Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.","volume":"110","author":"Hara","year":"2002","journal-title":"Cell"},{"key":"2020071612322083600_R34","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0960-9822(03)00329-4","article-title":"TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.","volume":"13","author":"Schalm","year":"2003","journal-title":"Curr Biol"},{"key":"2020071612322083600_R35","doi-asserted-by":"crossref","first-page":"15461","DOI":"10.1074\/jbc.C200665200","article-title":"The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.","volume":"278","author":"Nojima","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R36","doi-asserted-by":"crossref","first-page":"19667","DOI":"10.1074\/jbc.M301142200","article-title":"Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor.","volume":"278","author":"Choi","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R37","doi-asserted-by":"crossref","first-page":"11285","DOI":"10.1073\/pnas.1934283100","article-title":"Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.","volume":"100","author":"Matsuzaki","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612322083600_R38","first-page":"23","article-title":"A Foxo\/Notch pathway controls myogenic differentiation and fiber type specification.","volume":"23","author":"Kitamura","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071612322083600_R39","doi-asserted-by":"crossref","first-page":"40242","DOI":"10.1074\/jbc.M608116200","article-title":"Interaction of FoxO1 and TSC2 induces insulin resistance through activation of mTOR\/p70 S6K pathway.","volume":"281","author":"Cao","year":"2006","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R40","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/sj.emboj.7600945","article-title":"A novel ubiquitin-binding protein ZNF216 functioning in muscle atrophy.","volume":"25","author":"Hishiya","year":"2006","journal-title":"EMBO J"},{"key":"2020071612322083600_R41","doi-asserted-by":"crossref","first-page":"8189","DOI":"10.1128\/MCB.21.23.8189-8196.2001","article-title":"Regulatory mechanisms at the mouse Igf2\/H19 locus.","volume":"21","author":"Kaffer","year":"2001","journal-title":"Mol Cell Biol"},{"key":"2020071612322083600_R42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4161\/cbt.51","article-title":"Molecular pathogenesis of rhabdomyosarcoma.","volume":"1","author":"Xia","year":"2002","journal-title":"Cancer Biol Ther"},{"key":"2020071612322083600_R43","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.semcdb.2005.07.002","article-title":"The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis.","volume":"16","author":"Luo","year":"2005","journal-title":"Semin Cell Dev Biol"},{"key":"2020071612322083600_R44","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nature04940","article-title":"Notch signalling regulates stem cell numbers in vitro and in vivo.","volume":"442","author":"Androutsellis-Theotokis","year":"2006","journal-title":"Nature"},{"key":"2020071612322083600_R45","doi-asserted-by":"crossref","first-page":"21176","DOI":"10.1074\/jbc.M702039200","article-title":"FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle.","volume":"282","author":"Southgate","year":"2007","journal-title":"J Biol Chem"},{"key":"2020071612322083600_R46","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/ncb847","article-title":"Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling.","volume":"4","author":"Gao","year":"2002","journal-title":"Nat Cell Biol"},{"key":"2020071612322083600_R47","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cub.2005.02.053","article-title":"Rheb binds and regulates the mTOR kinase.","volume":"15","author":"Long","year":"2005","journal-title":"Curr Biol"},{"key":"2020071612322083600_R48","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/0092-8674(92)90643-Q","article-title":"Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases.","volume":"69","author":"Chung","year":"1992","journal-title":"Cell"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/3\/1407\/9003430\/endo1407.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/3\/1407\/9003430\/endo1407.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T08:14:12Z","timestamp":1684138452000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/149\/3\/1407\/2455314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12,13]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2007-1470","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12,13]]}}}