IN-VIVO ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES IN RAT INTESTINAL NEOPLASIA

Background & Aims: To investigate whether mitogen-activated protein ki nase (MAPK) cascades might play a role in the progression of colon can cer, c-Jun N-terminal kinase (JNK) and extracellular signal regulating kinase (ERK) activity during colonic tumorigenesis were examined. Met hods: The 1,2-dimethylhydrazine (DMH)-induced colon carcinoma model wa s used to study the activation of these kinases during intestinal carc inogenesis, Male Sprague-Dawley rats were injected with DMH for 24 wee ks. Normal-appearing intestinal mucosa from control and treated animal s and DMH-induced intestinal tumors were assayed for JNK and ERK activ ity using solid phase in vitro kinase assays. Tumors were typed for mu tations 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 J NK and ERK activities were observed, respectively, over control levels . In addition, activating protein-1 binding was strongly induced in th e colonic tumors. Activation did not correlate with the presence of mu tations in K-ras. Conclusions: Both the JNK and ERK MAPKs are highly a ctivated during late progression of colorectal carcinoma, This change is dependent on the tumorigenic state rather than changes in prolifera tion.