title: FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK.
abstract: Forkhead transcription factors of the FOXO class are negatively regulated by PKB/c-Akt in response to insulin/IGF signalling, and are involved in regulating cell cycle progression and cell death. Here we show that, in contrast to insulin signalling, low levels of oxidative stress generated by treatment with H2O2 induce the activation of FOXO4. Upon treatment of cells with H2O2, the small GTPase Ral is activated and this results in a JNK-dependent phosphorylation of FOXO4 on threonine 447 and threonine 451. This Ral-mediated, JNK-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of FOXO4 after H2O2 treatment. In addition, we show that this signalling pathway is also employed by tumor necrosis factor alpha to activate FOXO4 transcriptional activity. FOXO members have been implicated in cellular protection against oxidative stress via the transcriptional regulation of manganese superoxide dismutase and catalase gene expression. The results reported here, therefore, outline a homeostasis mechanism for sustaining cellular reactive oxygen species that is controlled by signalling pathways that can convey both negative (PI-3K/PKB) and positive (Ras/Ral) inputs.
authors.affiliation: Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marieke A G
authors.initials: MA
authors.lastname: Essers
authors.forename: Sanne
authors.initials: S
authors.lastname: Weijzen
authors.forename: Alida M M
authors.initials: AM
authors.lastname: de Vries-Smits
authors.forename: Ingrid
authors.initials: I
authors.lastname: Saarloos
authors.forename: Nancy D
authors.initials: ND
authors.lastname: de Ruiter
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.forename: Boudewijn M T
authors.initials: BM
authors.lastname: Burgering
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D007328:Insulin; D016877:Oxidants; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D013912:Threonine; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020725:ral GTP-Binding Proteins