Article
- The EMBO Journal (2004) 23, 4802 - 4812
- doi:10.1038/sj.emboj.7600476
Published online: 11 November 2004
Subject Categories:
FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK
Marieke AG Essers1,a, Sanne Weijzen1,a, Alida MM de Vries-Smits1,a, Ingrid Saarloos1, Nancy D de Ruiter2, Johannes L Bos1 and Boudewijn M T Burgering1
- Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
- Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA
Correspondence to:
Boudewijn M T Burgering, Department of Physiological Chemistry & Centre for Biomedical Genetics, University Medical Center Utrecht, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Tel.: +31 30 253 8918; Fax: +31 30 253 9035; E-mail: b.m.t.burgering@med.uu.nl
aThese authors contributed equally to this work
Received 14 June 2004; Accepted 13 October 2004
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 
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.
Keywords:
- FOXO,
- JNK,
- oxidative stress,
- Ral
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