Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence

Abstract

In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEKextracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.

Antagonistic control of cell fates by JNK and p38-MAPK signaling

“…Mouse embryonic fibroblasts (MEFs) isolated from mkk7 mutant embryos display impaired JNK and Jun activation, reduced cell proliferation, premature senescence, as well as augmented susceptibility to stressinduced aging ( Figure 1 and Wada et al 6 ). In contrast, activation of p38-MAPK can also result in premature senescence of MEFs, 7 whereas pharmacological p38-MAPK inhibition induces increased cell proliferation, 8 To assess functional hierarchies and potential molecular crosstalks between the JNK and p38-MAPK stress pathways in cell fate decisions, we tested the effects of p38-MAPK modulation in mkk7 À/À MEFs. Surprisingly, inhibition of p38-MAPKa/b using the selective inhibitor SB202190 restored the proliferation of mkk7-deficient MEFs to that of MKK7-expressing control cells (Figure 1a).…”

CpG- and LPS-activated MAPK signaling in in vitro cultured salmon (Salmo salar) mononuclear phagocytes

“…On the other hand, it should also be considered that SB203580 has potential to stimulate Raf1 [23]. This kinase is involved in ERK activation and a model has shown that it may also be involved in MKK6 phosphorylation [24]. Therefore the relatively fast SB203580-induced phosphorylation of salmon MKK6b/c and ERK may also be due to a direct positive effect of the inhibitor on Raf-1 or other upstream signalling components.…”

Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

“…The lack of involvement of p53 in BU-induced senescence prompted us to hypothesize that activation of the Erk-p38 MAPK pathway may mediate the induction, because activation of the Erk-p38 MAPK pathway has also been implicated in the induction of cellular senescence [13,15,34,35]. Indeed, it was found that treatment of WI38 cells with BU activated Erk and p38 in a time-dependent manner and inhibition of Erk or p38 with a specific inhibitor significantly suppressed BU-induced WI38 cell senescence.…”