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PMID: 15538382 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK.

The EMBO journal ·Vol. 23 ·No. 24 ·2004-12-08 ·Pages 4802-12

Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM

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.

MeSH Terms
14-3-3 Proteins/metabolism Animals Cell Cycle Proteins Cell Line Enzyme Activation Forkhead Transcription Factors Homeostasis Humans Hydrogen Peroxide/metabolism Insulin/metabolism JNK Mitogen-Activated Protein Kinases/genetics,metabolism Mice Mice, Knockout Oxidants/metabolism Oxidative Stress Phosphorylation Reactive Oxygen Species/metabolism Signal Transduction/physiology Threonine/metabolism Transcription Factors/genetics,metabolism Transcription, Genetic Tumor Necrosis Factor-alpha/metabolism ral GTP-Binding Proteins/genetics,metabolism
Chemicals
14-3-3 Proteins Cell Cycle Proteins FOXO4 protein, human Forkhead Transcription Factors Insulin Oxidants Reactive Oxygen Species Transcription Factors Tumor Necrosis Factor-alpha Threonine Hydrogen Peroxide JNK Mitogen-Activated Protein Kinases ral GTP-Binding Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Essers Marieke A G
Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Weijzen Sanne
de Vries-Smits Alida M M
Saarloos Ingrid
de Ruiter Nancy D
Bos Johannes L
Burgering Boudewijn M T
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600476
Published
2004-12-08
Epub
2004-00-11
Pages
4802-12
Language
English
Region
England
NLM ID
8208664
PMCID
PMC535088
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600476 PMC Full Text View journal details
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