In vivo activation of mitogen-activated protein kinases in rat intestinal neoplasia.
OBJECTIVE
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.
Licato
L L
LL
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill 27599, USA.
Keku
T O
TO
Wurzelmann
J I
JI
Murray
S C
SC
Woosley
J T
JT
Sandler
R S
RS
Brenner
D A
DA
D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D004789:Enzyme Activation; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism
D009419:Nerve Tissue Proteins; D018808:Transcription Factor AP-1; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019813:1,2-Dimethylhydrazine