Korean Diabetes Journal 2005;29(4):295-303.
Published online July 1, 2005.
The Role of cAMP/PKA Activation on Exendin-4-Induced Cyclin D1 Expression in INS-1 Cell.
Gyeong Ryul Ryu, Jung Hoon Kang, Hwa In Jang, Seung Hyun Ko, In Kyung Jeong, Duck Joo Rhie, Shin Hee Yoon, Sang June Hahn, Yang Hyeok Jo, Myung Suk Kim, Myung Jun Kim
1Departments of Physiology and Internal Medicine1, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
2Department of Internal Medicine, College of Medicine, Hallym University, Seoul 150-030, Korea.
Glucagon-like peptide-1(GLP-1) and exendin-4(EX-4) have been known to induce pancreatic islet proliferation and increases in the betacell mass. Cyclin D1 is a key protein responsible for the entry of the G into the S phase, thereby contributing to cell proliferation. Therefore, the effect of EX-4 on the expression of cyclin D1 in INS-1 cells, a rat pancreatic betacell line, was investigated. The involvement of either mitogen-activated protein kinases(MAPKs) or cyclic adenosine 5'-monophosphate/protein kinase A(cAMP/ PKA) in the EX-4-induced cyclin D1 expression was also examined. METHODS: INS-1 cells were treated with EX-4 (10 nM), and the cyclin D1 protein levels then determined by Western blot. To investigate the involvement of MAPKs in the EX-4- induced cyclin D1 expression, either a combined treatment of MAPKs inhibitors or transient transfection of extracellular signal-regulated kinase-1 (ERK1) was performed. The effect of cAMP on the EX-4-induced cyclin D1 expression was also examined by treatments with forskolin, an adenylyl cyclase activator, and H-89, a PKA inhibitor. RESULTS: EX-4 increased the expression of cyclin D1 protein in a dose-dependent manner. Although EX-4 induced phosphorylation of ERK1/2, the treatment with PD 98059 or the overexpression of ERK1 had no effect on the EX-4-induced cyclin D1 expression. However, forskolin significantly induced the expression of cyclin D1, whereas the pretreatment of H-89 inhibited the EX-4-induced cyclin D1 expression. CONCLUSION: These results suggest that EX-4 induce cyclin D1 expression in INS-1 cells via cAMP/PKA pathway, but this is not due to ERK activation.
Key Words: Exendin-4, INS-1, Cyclin D1, cAMP/PKA, ERK

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