Parekh V V, Hoffman J L, Younoszai M K
Department of Pediatrics, University of Louisville School of Medicine, KY 40292, USA.
J Investig Med. 1998 Feb;46(2):76-81.
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.
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.
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.
肠道快速增殖细胞的不同信号转导途径尚未完全明确。我们在此报告一条可能的信号通路，该通路在糖尿病空肠黏膜增生过程中涉及对两种密切相关激酶——丝裂原活化蛋白激酶（MAP-K）和p34cdc2激酶活性的调节。我们的目的是在体内研究糖尿病诱导的空肠黏膜增生过程中MAP-K的活性和磷酸化以及p34cdc2激酶的活性及其与细胞周期蛋白B的结合情况。
我们研究了未经处理和经二氟甲基鸟氨酸（DFMO）处理的对照大鼠以及链脲佐菌素诱导的I型糖尿病大鼠。在诱导糖尿病10天后进行检测。与对照大鼠的相应值相比，糖尿病大鼠出现空肠增生，表现为空肠黏膜重量/厘米和DNA含量增加，以及MAP-K和p34cdc2激酶活性增加，且后者与细胞周期蛋白B结合。给予DFMO（一种增殖相关酶鸟氨酸脱羧酶（ODC）的不可逆抑制剂）可预防糖尿病I诱导的空肠增生，并降低糖尿病大鼠和对照大鼠的所有上述酶学参数。在我们之前的体内研究中，给予DFMO也可阻断糖尿病空肠增生，此外还可降低空肠鸟氨酸脱羧酶和酪氨酸激酶活性以及蛋白质的酪氨酸磷酸化。
因此，糖尿病中发现的空肠黏膜增生似乎涉及酪氨酸激酶、MAP-K、p34cdc2激酶和细胞周期蛋白B参与的信号转导途径的激活。
