Tschen Shuen-Ing, Georgia Senta, Dhawan Sangeeta, Bhushan Anil
Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095-7073, USA.
Mol Endocrinol. 2011 Dec;25(12):2134-43. doi: 10.1210/me.2011-1119. Epub 2011 Oct 6.
The glucoincretin hormone glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (Ex-4) promote β-cell growth and expansion. Here we report an essential role for Skp2, a substrate recognition component of SCF (Skp, Cullin, F-box) ubiquitin ligase, in promoting glucoincretin-induced β-cell proliferation by regulating the cellular abundance of p27. In vitro, GLP-1 treatment increases Skp2 levels, which accelerates p27 degradation, whereas in vivo, loss of Skp2 prevents glucoincretin-induced β-cell proliferation. Using inhibitors of phosphatidylinositol 3-kinase and Irs2 silencing RNA, we also show that the effects of GLP-1 in facilitating Skp2-dependent p27 degradation are mediated via the Irs2-phosphatidylinositol-3 kinase pathway. Finally, we show that down-regulation of p27 occurs in islets from aged mice and humans, although in these islets, age-dependent accumulation of p16(Ink4a) prevent glucoincretin-induced β-cell proliferation; however, ductal cell proliferation is maintained. Taken together, these data highlight a critical role for Skp2 in glucoincretin-induced β-cell proliferation.
胰高血糖素样肽-1（GLP-1）及其类似物艾塞那肽-4（Ex-4）等胰高糖素样肽激素可促进β细胞生长和增殖。在此，我们报告了Skp2（SCF（Skp、Cullin、F-box）泛素连接酶的底物识别成分）在通过调节p27的细胞丰度来促进胰高糖素样肽诱导的β细胞增殖中发挥的重要作用。在体外，GLP-1处理可提高Skp2水平，从而加速p27降解；而在体内，Skp2缺失则会阻止胰高糖素样肽诱导β细胞增殖。使用磷脂酰肌醇3激酶抑制剂和Irs2沉默RNA，我们还表明GLP-1促进Skp2依赖的p27降解的作用是通过Irs2-磷脂酰肌醇-3激酶途径介导的。最后，我们发现老年小鼠和人类胰岛中p27表达下调，尽管在这些胰岛中，p16（Ink4a）的年龄依赖性积累会阻止胰高糖素样肽诱导的β细胞增殖，但导管细胞增殖得以维持。综上所述，这些数据突出了Skp2在胰高糖素样肽诱导的β细胞增殖中的关键作用。
