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 proliferating cells of the intestine are not clearly understood. We report here a possible signaling pathway that involves regulation of activity of two closely related kinases, MAP-K (mitogen-activated protein kinase) and p34cdc2 kinase, during hyperplasia of diabetic jejunal mucosa. Our aim was to investigate the activity and phosphorylation of MAP-K and activity and association of p34cdc2 kinase with cyclin B during diabetes-induced jejunal mucosal hyperplasia in vivo.


METHODS
We studied untreated and difluoromethylornithine (DFMO) treated control rats and rats with streptozotocin-induced type I diabetes. Assays were done 10 days after the induction of diabetes. In diabetic rats there was jejunal hyperplasia as indicated by increases in the jejunal mucosal weight/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 irreversible 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 and control rats. In our previous in vivo study, DFMO administration also blocked diabetic jejunal hyperplasia and in addition decreased ornithine decarboxylase and tyrosine kinase activities jejunal and tyrosine phosphorylation of proteins.


CONCLUSIONS
Thus the jejunal mucosal hyperplasia found in diabetes appears to involve activation of signal transduction pathways involving tyrosine kinases, MAP-K, p34cdc2 kinase, and cyclin B.
Parekh
V V
VV
Department of Pediatrics, University of Louisville School of Medicine, KY 40292, USA.
Hoffman
J L
JL
Younoszai
M K
MK
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006965:Hyperplasia; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007583:Jejunum / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D019926:Cyclin B; D004791:Enzyme Inhibitors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D000518:Eflornithine