Related Experiment Video

Updated: Aug 21, 2026

Measurements of Physiological Stress Responses in C. Elegans
10:36

Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

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

Marieke A G Essers1, Sanne Weijzen, Alida M M de Vries-Smits

  • 1Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

The EMBO Journal
|November 13, 2004
PubMed

Insights

Oxidative stress activates FOXO4 transcription factor via Ral and JNK signaling, contrasting insulin pathways. This regulates cellular reactive oxygen species, impacting cell protection and homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Transcription Factors

Background:

  • FOXO (forkhead box) transcription factors are key regulators of cell cycle and apoptosis.
  • Insulin/IGF signaling negatively regulates FOXO activity via PKB/c-Akt.
  • Cellular response to oxidative stress involves FOXO-mediated gene expression.

Purpose of the Study:

  • To investigate the regulation of FOXO4 by oxidative stress.
  • To elucidate the signaling pathway mediating FOXO4 activation under oxidative stress.
  • To understand the role of FOXO4 in cellular reactive oxygen species homeostasis.

Main Methods:

  • Hydrogen peroxide (H2O2) treatment to induce oxidative stress.
  • Analysis of small GTPase Ral activation.
  • JNK-dependent phosphorylation assays for FOXO4.
  • Western blotting and immunofluorescence for nuclear translocation.
  • Reporter assays for transcriptional activation.

Main Results:

  • Low levels of H2O2 induce FOXO4 activation, distinct from insulin signaling.
  • H2O2 activates Ral, leading to JNK-dependent phosphorylation of FOXO4 at Thr447/451.
  • This phosphorylation promotes FOXO4 nuclear translocation and transcriptional activity.
  • Tumor necrosis factor alpha also utilizes this pathway to activate FOXO4.
  • FOXO4 regulates genes like manganese superoxide dismutase and catalase.

Conclusions:

  • A novel signaling pathway involving Ral and JNK mediates FOXO4 activation by oxidative stress.
  • This pathway contributes to cellular reactive oxygen species homeostasis.
  • FOXO4 acts as a critical node integrating signals from insulin/IGF and oxidative stress pathways.

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...