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 H 2 O 2 induce the activation of FOXO4. Upon treatment of cells with H 2 O 2 , 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 H 2 O 2 treatment. In addition, we show that this signalling pathway is also employed by tumor necrosis factor a 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.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…As high and very low levels of ROS lead to impaired cellular functions, maintaining intracellular ROS homeostasis is essential to prevent pathological processes including cancer and other age‐associated diseases. FOXOs are regulated by oxidative stress via changes in upstream FOXO regulatory pathways or directly sensing the cellular redox status through reversible oxidation and reduction of cystein residues (Essers et al ., 2004; Eijkelenboom & Burgering, 2013; Putker et al ., 2013). FOXO factors regulate the expression of the key detoxification enzymes MnSOD (manganese superoxide dismutase), catalase, and GADD45 (Kops et al ., 2002; Nemoto & Finkel, 2002).…”

Post-translational modifications of FOXO family proteins

“…Furthermore, the MST1-FOXO pathway has a significant role in drug treatment-induced cancer cell death (38). When cells are under to oxidative stress, the JNK-dependent signaling pathway causes phosphorylation of FOXO4, thereby inducing FOXO4 nuclear translocation and activity (39). JNK mediates the FOXO activity via the correct assembly of JNK interacting protein 1 (JIP1) complexes, which includes three substrates, mitogen-activated protein kinase (MAPK) kinase kinase 11, MAPK kinase 4 and JNK.…”

The FoxO transcription factors and metabolic regulation

“…Furthermore, it has been demonstrated that JNK-1 directly interacts with, phosphorylates, enhances nuclear localization of DAF-16, and induces its target gene expression [24]. Indeed, low levels of oxidative stress generated by treatment with H 2 O 2 activates the small GTPase Ral and induce a JNK-dependent phosphorylation of Threonine 447 and Threonine451, nuclear translocation, and transcriptional activation of FOXO4 [26].…”