title: Regulation of the intracellular localization of Foxo3a by stress-activated protein kinase signaling pathways in skeletal muscle cells.
abstract: Muscle atrophy is a debilitating process associated with many chronic wasting diseases, like cancer, diabetes, sepsis, and renal failure. Rapid loss of muscle mass occurs mainly through the activation of protein breakdown by the ubiquitin proteasome pathway. Foxo3a transcription factor is critical for muscle atrophy, since it activates the expression of ubiquitin ligase Atrogin-1. In several models of atrophy, inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway induces nuclear import of Foxo3a through an Akt-dependent process. This study aimed to identify signaling pathways involved in the control of Foxo3a nuclear translocation in muscle cells. We observed that after nuclear import of Foxo3a by PI3K/Akt pathway inhibition, activation of stress-activated protein kinase (SAPK) pathways induced nuclear export of Foxo3a through CRM1. This mechanism involved the c-Jun NH(2)-terminal kinase (JNK) signaling pathway and was independent of Akt. Likewise, we showed that inhibition of p38 induced a massive nuclear relocalization of Foxo3a. Our results thus suggest that SAPKs are involved in the control of Foxo3a nucleocytoplasmic translocation in C2C12 cells. Moreover, activation of SAPKs decreases the expression of Atrogin-1, and stable C2C12 myotubes, in which the p38 pathway is constitutively activated, present partial protection against atrophy.
authors.affiliation: Université de Nice Sophia Antipolis EA 4319/INSERM ERI-21, 28 Avenue de Valombrose, 06108 Nice Cedex 2, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Clavel
authors.forename: Sandrine
authors.initials: S
authors.lastname: Siffroi-Fernandez
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Coldefy
authors.forename: Kim
authors.initials: K
authors.lastname: Boulukos
authors.forename: Didier F
authors.initials: DF
authors.lastname: Pisani
authors.forename: Benoît
authors.initials: B
authors.lastname: Dérijard
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D028884:Karyopherins / Q000187:drug effects / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D000873:Anthracenes; D002867:Chromones; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007546:Isoquinolines; D028884:Karyopherins; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D044843:SKP Cullin F-Box Protein Ligases; D013449:Sulfonamides; D013876:Thiophenes; D048051:p38 Mitogen-Activated Protein Kinases; D000097606:Exportin 1 Protein; C499517:FOXO3 protein, human; C477523:SC 514; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C486691:Fbxo32 protein, mouse; C482531:Map2k3 protein, mouse; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide