This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suh, Y. Articles by Park, J.-B. Search for Related Content PubMed PubMed Citation Articles by Suh, Y. Articles by 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 Carcinogenesis¹

Departments of Biochemistry and Molecular Biology [Y. S., S-C. P.], Psychiatry [U. G. K., Y. S. K.], and Pathology [W-H. K.] and Cancer Research Center [Y. S., W-H. K., J-B. P.], Seoul National University College of Medicine, Seoul 110-799, Korea, and Department of Molecular Cell Biology, and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea [J-B. P.]

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.

This article has been cited by other articles:

				R. A. Busuttil, A. M. Garcia, C. Cabrera, A. Rodriguez, Y. Suh, W. H. Kim, T.-T. Huang, and J. Vijg Organ-Specific Increase in Mutation Accumulation and Apoptosis Rate in CuZn-Superoxide Dismutase-Deficient Mice Cancer Res., December 15, 2005; 65(24): 11271 - 11275. [Abstract] [Full Text] [PDF]