Differential activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinases by methyl methanesulfonate in the liver and brain of rats: Implication for organ-specific carcinogenesis

Methyl methanesulfonate (MMS), a direct-acting alkylating agent, is a stron g brain carcinogen but a poor hepatocarcinogen in rats. To elucidate the me chanism(s) leading to tissue-specific carcinogenesis in response to MMS, we compared the activation of the stress-activated protein kinases (SAPKs), t he c-Jun NH2-terminal kinase (JNK) and p38, in the liver and brain of rats after i.p. injection of MMS, p38 was activated in both the liver and brain, but JNK was activated only in the liver in a dose- and time-dependent mann er. The activation of JNK was preceded by the activation of SAPK or extrace llular signal-regulated protein kinase kinase 1/mitogen-activated protein k inase kinase 4 in the liver, but no activation of SAPK or extracellular sig nal-regulated protein kinase kinase 1/mitogen-activated protein kinase kina se 4 was observed in the brain. The activation of JNK in the liver was acco mpanied by increased phosphorylation of activating transcription factor 2 a nd followed by an increase in the phosphorylation and level of c-Jun protei n, in contrast to no such changes in the brain. To study the physiological consequences of these differential molecular events in the liver and brain, we examined MMS-induced apoptosis, a process shown to involve stress kinas e activation. A significant increase in apoptotic cell death was detected i n the liver but not in the brain after a MMS injection, which correlated wi th the patterns of JNK activation in the liver, Taken together, our results demonstrate that a tissue-specific signaling pathway(s) leading to distinc t physiological responses in the liver and brain of rats exposed to MMS exi sts, suggesting a possible explanation for tissue-specific carcinogenic eff ects exerted by MMS in vivo.