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

Yousin Suh, Gu Kang Ung Gu Kang, Sik Kim Yong Sik Kim, W. H. Kim, S. C. Park, J. B. Park

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Methyl methanesulfonate (MMS), a direct-acting alkylating agent, is a strong brain carcinogen but a poor hepatocarcinogen in rats. To elucidate the mechanism(s) leading to tissue-specific carcinogenesis in response to MMS, we compared the activation of the stress-activated protein kinases (SAPKs), the 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 manner. The activation of JNK was preceded by the activation of SAPK or extracellular signal-regulated protein kinase kinase 1/mitogen-activated protein kinase kinase 4 in the liver, but no activation of SAPK or extracellular signal-regulated protein kinase kinase 1/mitogen-activated protein kinase kinase 4 was observed in the brain. The activation of JNK in the liver was accompanied by increased phosphorylation of activating transcription factor 2 and followed by an increase in the phosphorylation and level of c-Jun protein, 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 kinase activation. A significant increase in apoptotic cell death was detected in the liver but not in the brain after a MMS injection, which correlated with the patterns of JNK activation in the liver. Taken together, our results demonstrate that a tissue-specific signaling pathway(s) leading to distinct physiological responses in the liver and brain of rats exposed to MMS exists, suggesting a possible explanation for tissue-specific carcinogenic effects exerted by MMS in vivo.

Original languageEnglish (US)
Pages (from-to)5067-5073
Number of pages7
JournalCancer Research
Volume60
Issue number18
StatePublished - Sep 15 2000
Externally publishedYes

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Methyl Methanesulfonate
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Carcinogenesis
Liver
Brain
Protein Kinases
MAP Kinase Kinase Kinase 4
Heat-Shock Proteins
MAP Kinase Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Activating Transcription Factor 2
Phosphorylation
Proto-Oncogene Proteins c-jun
Injections
Alkylating Agents
Carcinogens
Cell Death
Phosphotransferases
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Suh, Yousin; Ung Gu Kang, Gu Kang; Yong Sik Kim, Sik Kim; Kim, W. H.; Park, S. C.; Park, J. B.

In: Cancer Research, Vol. 60, No. 18, 15.09.2000, p. 5067-5073.

Research output: Contribution to journalArticle

Suh, Yousin ; Ung Gu Kang, Gu Kang ; Yong Sik Kim, Sik Kim ; Kim, W. H. ; Park, S. C. ; Park, J. B. / 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. In: Cancer Research. 2000 ; Vol. 60, No. 18. pp. 5067-5073.
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