EFFECTS OF DIABETES AND DIFLUOROMETHYLORNITHINE TREATMENT ON HYPERPLASIA, ACTIVITY OF MAP-KINASE, AND ACTIVITY AND ASSOCIATION WITH CYCLIN-B OF P34CDC2 KINASE IN RAT JEJUNAL MUCOSA

Background: The different signal transduction pathways of rapidly prol iferating cells of the intestine are not clearly understood, We report here a possible signaling pathway that involves regulation of activit y of two closely related kinases, MAP-K (mitogen-activated protein kin ase) and p34cdc2 kinase, during hyperplasia of diabetic jejunal mucosa , Our aim was to investigate the activity and phosphorylation of MAP-I I and activity and association of p34cdc2 kinase with cyclin B during diabetes-induced jejunal mucosal hyperplasia in vivo. Methods: We stud ied untreated and difluoromethylornithine (DFMO) treated control rats and rats with streptozo-tocin-induced type I diabetes, Assays were don e 10 days after the induction of diabetes, In diabetic rats there was jejunal hyperplasia as indicated by increases in the jejunal mucosal w eight/cm and DNA content as well as increased activities of MAP-K and p34cdc2 kinase and association of the latter with cyclin B as compared to corresponding values in control rats, Administration of DFMO, an i rreversible inhibitor of the proliferation-associated enzyme ornithine decarboxylase (ODC), prevented diabetes-I induced jejunal hyperplasia and decreased all of the above enzymic parameters in both diabetic an d control rats, In our previous in vivo study, DFMO administration als o blocked diabetic jejunal hyperplasia and in addition decreased ornit hine decarboxylase and tyrosine kinase activities jejunal and tyrosine phosphorylation of proteins. Conclusion: Thus the jejunal mucosal hyp erplasia found in diabetes appears to involve activation of signal tra nsduction pathways involving tyrosine kinases, MAP-K, p34cdc2 kinase, and cyclin B.