Rapamycin Inhibits Growth Factor-Induced Cell Cycle Regulation in Pancreatic β Cells
Rapamycin Inhibits Growth Factor-Induced Cell Cycle Regulation in Pancreatic β Cells
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DOI：
10.2310/jim.0b013e31818ce763
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发表时间：
2008-12-01
影响因子：
2.6
通讯作者：
Lowe, William L., Jr.
中科院分区：
文献类型：
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作者：
Aronovitz, Amy;Josefson, Jami;Lowe, William L., Jr.
胰岛功能的进行性衰退是胰岛移植成功的主要障碍。胰岛功能下降的原因尚不清楚，但免疫抑制剂可能有所贡献。胰岛素样生长因子-I (IGF-I) 和β细胞素对于胰岛细胞的存活和/或增殖很重要。在本研究中，我们在 INS-1 细胞和小鼠胰岛中进行了研究，以确定 IGF-I 和 betacellulin 对胰岛细胞在细胞周期中进展的影响以及免疫抑制剂的影响。用 20 ng/mL βcellulin 或 50 ng/mL IGF-I 处理 INS-1 细胞 24 小时，S 期细胞数量增加了约 2 倍。用 IGF-I 或 betacellulin 处理 INS-1 细胞也增加了细胞周期蛋白 D 1 的表达以及细胞周期蛋白依赖性激酶抑制剂 p21(Cip1) 和 p27(Kip1) 的核排除。在 INS-1 细胞和胰岛中，βcellulin 和 IGF-I 增加 Akt、细胞外信号相关激酶和 p70(S6)（激酶）磷酸化。雷帕霉素是一种抑制哺乳动物雷帕霉素靶标的免疫抑制剂，可抑制 INS-1 细胞中由 betacellulin 和 IGF-I 刺激的 p70(S6)（激酶）磷酸化的增加。 Rapamycin 还抑制 betacellulin 和 IGF-I 诱导的细胞进入 S 期和 5'-Bromo-2'-deoxyuridine 掺入，以及 betacellulin 和 IGF-I 对细胞周期蛋白 D1 表达以及 p21(Cip1) 和 p27(Kip1) 核排除的影响。总之，这些数据表明β细胞素和IGF-I对胰岛细胞生长和增殖的影响部分是通过哺乳动物雷帕霉素靶标的信号传导介导的。由于雷帕霉素用于治疗胰岛移植受者，这些结果表明，随着时间的推移，雷帕霉素可能对胰岛增殖和功能产生有害影响。
A progressive decline in islet function is a major obstacle to the success of islet transplantation. The cause of this decline in islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies in INS-1 cells and murine islets to define the effect of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hours with 20 ng/mL betacellulin or 50 ng/mL IGF-I increased cells in S phase by similar to 2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D 1 expression and nuclear exclusion of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1). In INS-1 cells and islets, betacellulin- and IGF-I increased Akt, extracellular signal-related kinase, and p70(S6) (kinase) phosphorylation. Rapamycin, an immunosuppressant which inhibits mammalian target of rapamycin, inhibited the increase in p70(S6) (kinase) phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and 5'-Bromo-2'-deoxyuridine incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21(Cip1) and p27(Kip1). Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mammalian target of rapamycin. As rapamycin is used to treat islet transplant recipients, these results suggest that rapamycin could have deleterious effects on islet proliferation and function over time.