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

In contrast to insulin signalling, low levels of oxidative stress generated by treatment with H2O2 induce the activation of FOXO4

Marieke A G Essers; Sanne Weijzen; Alida M M de Vries-Smits; Ingrid Saarloos; Nancy D de Ruiter; Johannes L Bos; Boudewijn M T Burgering


Scholarcy highlights

  • Reactive oxygen species are oxygen free radicals that are highly reactive toward cellular constituents including protein, lipid and DNA
  • To investigate whether FOXO could function in a feedback mechanism to control cellular redox, we first analyzed the possibility that, similar to insulin signalling, cellular oxidative stress generated by H2O2 treatment of cells could induce FOXO phosphorylation
  • The T447P antibody did not recognize HA-FOXO4-T451A, suggesting that threonine 451 is an essential part of the epitope for the T447P antibody
  • These results show that in vivo FOXO4 becomes phosphorylated at threonine 447 and T451 following treatment of cells with H2O2
  • manganese superoxide dismutase and catalase belong to a large and diverse family of antioxidant enzymes. Their regulation via PI-3K/PKB/FOXO signalling implies that insulin, through this signalling cascade, may modulate the cellular ROS level. Consistent with this hypothesis, we have previously shown that FOXO-mediated upregulation of MnSOD expression results in considerable lowering of cellular ROS
  • Active JNK induces the phosphorylation of T447 and T451 on FOXO4
  • Taken together and consistent with our own data on the role of acetylation in regulating FOXO4, the data presented here suggest that during periods of low oxidative stress, FOXOs are initially activated by JNK-mediated phosphorylation, but thereafter or at higher concentrations or longer periods of time inactivated by acetylation and/or ubiquitination

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