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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.
Cancer Res. 2000 Sep 15; 60(18):5067-73.CR

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11016630

Citation

Suh, Y, et al. "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." Cancer Research, vol. 60, no. 18, 2000, pp. 5067-73.
Suh Y, Kang UG, Kim YS, et al. 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. Cancer Res. 2000;60(18):5067-73.
Suh, Y., Kang, U. G., Kim, Y. S., Kim, W. H., Park, S. C., & Park, J. B. (2000). 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. Cancer Research, 60(18), 5067-73.
Suh Y, et al. 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. Cancer Res. 2000 Sep 15;60(18):5067-73. PubMed PMID: 11016630.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Suh,Y, AU - Kang,U G, AU - Kim,Y S, AU - Kim,W H, AU - Park,S C, AU - Park,J B, PY - 2000/10/4/pubmed PY - 2000/10/21/medline PY - 2000/10/4/entrez SP - 5067 EP - 73 JF - Cancer research JO - Cancer Res. VL - 60 IS - 18 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11016630/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_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11016630 DB - PRIME DP - Unbound Medicine ER -