Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H₂O₂

Abstract

Stimulation of cell signaling cascades by oxidants may be important in the pathogenesis of pulmonary and pleural diseases. Here, we demonstrate in rat pleural mesothelial cells that apoptotic concentrations of crocidolite asbestos and H2O2induce phosphorylation and activation of extracellular signal-regulated protein kinases (ERK). Activation of c- jun-NH2-terminal protein kinases (JNK)/stress-activated protein kinases was also observed in response to H2O2. In contrast, asbestos caused more protracted activation of ERK without JNK activation. Both H2O2- and asbestos-induced activation of ERK was abolished by catalase. Moreover, chelation of surface iron from crocidolite fibers or addition of N-acetyl-l-cysteine prevented ERK activation and apoptosis by crocidolite, indicating an oxidative mechanism of cell signaling. The MEK1 inhibitor PD-98059 abrogated asbestos-induced apoptosis, confirming a causal relationship between ERK activation and apoptosis. These results suggest that distinct cell-signaling cascades may be important in phenotypic responses elicited by oxidant stresses.

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.…”

Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epithelial cells

“…47 In contrast to the JNK pathway, most studies indicate that activation of extracellular regulated kinases (ERKs) protects against apoptosis, 31,48,49 while more limited data suggest a role for ERK activation in promoting apoptosis. [50][51][52] Indeed, we have previously shown that ERK is inactivated in parotid C5 cells induced to undergo apoptosis by treatment with etoposide 46 or TPA. 15 However, the data presented in the current manuscript show that apoptosis associated with PKCa inhibition correlates with an increase in the expression of ERK1 and ERK2 protein as well as an increase in the abundance of the phosphorylated or activated forms of these kinases.…”

Cellular response to oxidative stress: Signaling for suicide and survival*

“…However, other studies using different model systems have produced findings to suggest that ERK activation can contribute to apoptosis in response to oxidant injury. These include hyperoxiainduced apoptosis of macrophages (Petrache et al, 1999), cisplatin-induced apoptosis of HeLa cells , hydrogen peroxide-induced apoptosis of oligodendrocytes (Bhat and Zhang, 1999;Brand et al, 2001) and mesengial cells (Ishikawa and Kitamura, 2000), and asbestos-induced apoptosis of pleural mesothelial cells (Jimenez et al, 1997). What determines whether ERK will act in a pro-apoptotic or anti-apoptotic fashion remains an important unanswered question, but the kinetics and duration of its activation may be important factors.…”

“…What determines whether ERK will act in a pro-apoptotic or anti-apoptotic fashion remains an important unanswered question, but the kinetics and duration of its activation may be important factors. For example, in situations where ERK activity enhances survival, activation occurs rapidly and is more transient (Guyton et al, 1996a,b;Aikawa et al, 1997;Ikeyama et al, 2000), in situations where it is apoptotic, activation tends to be delayed and sustained (Jimenez et al, 1997;Wang et al, 2000a).…”