In vivo activation of mitogen-activated protein kinases in rat intestinal neoplasia

Gastroenterology. 1997 Nov;113(5):1589-98. doi: 10.1053/gast.1997.v113.pm9352861.

Abstract

Background & aims: To investigate whether mitogen-activated protein kinase (MAPK) cascades might play a role in the progression of colon cancer, c-Jun N-terminal kinase (JNK) and extracellular signal regulating kinase (ERK) activity during colonic tumorigenesis were examined.

Methods: The 1,2-dimethylhydrazine (DMH)-induced colon carcinoma model was used to study the activation of these kinases during intestinal carcinogenesis. Male Sprague-Dawley rats were injected with DMH for 24 weeks. Normal-appearing intestinal mucosa from control and treated animals and DMH-induced intestinal tumors were assayed for JNK and ERK activity using solid phase in vitro kinase assays. Tumors were typed for mutations in the K-ras gene.

Results: There was little or no difference in JNK and ERK activity in hyperproliferative mucosa from DMH-treated animals compared with normal mucosa from control animals. However, in 16 colonic neoplasms, an average of 23-fold and 29-fold increases in JNK and ERK activities were observed, respectively, over control levels. In addition, activating protein-1 binding was strongly induced in the colonic tumors. Activation did not correlate with the presence of mutations in K-ras.

Conclusions: Both the JNK and ERK MAPKs are highly activated during late progression of colorectal carcinoma. This change is dependent on the tumorigenic state rather than changes in proliferation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1,2-Dimethylhydrazine / toxicity
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / enzymology*
  • Enzyme Activation
  • Genes, ras
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Male
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases / biosynthesis
  • Mutation
  • Nerve Tissue Proteins / biosynthesis
  • Protein Kinases / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factor AP-1 / metabolism

Substances

  • Nerve Tissue Proteins
  • Transcription Factor AP-1
  • Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • 1,2-Dimethylhydrazine