The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival

Abstract

The mammalian response to stress is complex, often involving multiple signalling pathways that act in concert to influence cell fate. To examine potential interactions between the signalling cascades, we have focused on the effects of a model oxidant stress in a single cell type through an examination of the relative influences of mitogen-activated protein kinases (MAPKs) as well as two proposed apoptosis regulators, nuclear factor kappaB (NF-kappaB) and Bcl-2, in determining cell survival. Treatment of HeLa cells with H2O2 resulted in a time- and dose-dependent induction of apoptosis accompanied by sustained activation of all three MAPK subfamilies: extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. This H2O2-induced apoptosis was markedly enhanced when ERK2 activation was selectively inhibited by PD098059. Apoptosis decreased when JNK/SAPK activation was inhibited by expression of a dominant negative mutant form of SAPK/ERK kinase 1. Inhibition of the p38 kinase activity with p38-specific inhibitors SB202190 and SB203580 had no effect on cell survival. Because NF-kappaB activation by H2O2 is potentially related to both the ERK and JNK/SAPK signalling pathways, we examined the effects of inhibiting the activation of NF-kappaB; this interference had no effect on the cellular response to H2O2. Overexpression of the anti-apoptotic protein Bcl-2 significantly decreased the apoptosis seen after treatment with H2O2 without altering ERK or JNK/SAPK activities. Our results suggest that ERK and JNK/SAPK act in opposition to influence cell survival in response to oxidative stress, whereas neither p38 nor NF-kappaB affects the outcome. Bcl-2 acts independently and downstream of ERK and JNK/SAPK to enhance the survival of H2O2-treated cells.

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

“…Our results suggest that STC1 functions in a negative feedback loop to regulate MEK and ERK1/2. The higher levels of activated MEK and ERK1/2 in STC1À/À MEFs were associated with resistance to oxidative stress, in agreement with the observation that ERK1/2 has a mitogenic or prosurvival function (Wang et al, 1998). Therefore, the MEK-ERK1/2-STC1 negative feedback loop downregulates the ERK1/2 prosurvival signaling pathway and decreases survival of MEFs in response to oxidative stress.…”

“…The ERK family of proteins play central roles in regulating the survival of cells in response to oxidative stress (Wang et al, 1998), so we examined whether altered ERK1/2 signaling might account for the resistance of STC1À/À MEFs to oxidative stress. Western blot analysis for phosphorylated ERK1/2 revealed that STC1À/À MEFs had higher levels of activated ERK1/2 than STC1 þ / þ MEFs (Figure 4a), but total ERK1/2 protein levels in STC1 þ / þ and STC1À/À MEFs were similar (Figure 4a).…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…Growth factor receptors have been shown to undergo enhanced phosphorylation in response to oxidative insults like hydrogen peroxide or UV-radiation initiating ERK1/2 activation [115,116,210]. This is consistent with demonstrations of the mitogenic effects of low concentrations of hydrogen peroxide [23].…”

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

“…Results illustrated that, despite high expression, MEK1/2 and ERK1/2 proteins were mainly unphosphorylated in untreated NCCIT cells (Figure 3). However, phosphorylation of MEK1/2 and ERK1/2 proteins began to increase at 6 h and was at its highest at 12 h after CDDP treatment, a course which has been observed in growth factor-or oxidantmediated MEK -ERK activation in many cell types (Jimenez et al, 1997;Wang et al, 1998). Interestingly, MEK1 and ERK2 seem to be more strongly phosphorylated than MEK2 and ERK1.…”