Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Islets. 2013 Jan-Feb;5(1):22-8. doi: 10.4161/isl.24029. Epub 2013 Jan 1.
Functional β-cell mass deficiency in diabetes results from imbalanced β-cell death and replication, and decreased PAK1 protein levels in human islets from donors with type 2 diabetes implicates a possible role for PAK1 in maintaining β-cell mass. Here, we aim to address the linkage between PAK1 and Survivin, a protein essential for β-cell replication. PAK1 knockout (KO) mouse islets exhibited decreased expression of Survivin protein. MIN6 β-cells with siRNA-mediated suppression of PAK1 also had decreased Survivin protein and exhibited an increased level of ubiquitinated-Survivin. However, no significant changes in Survivin mRNA were found in islets from PAK1 KO mice and PAK1-depleted MIN6 β-cells. The decreased Survivin level in MIN6 cells subjected to hyperglycemic stress was prevented by expression of exogenous PAK1. Moreover, overexpressing Survivin restored proliferation of β-cells that was impaired by the loss of PAK1. These data implicate a role for PAK1 in regulating Survivin protein stability in the β-cell and suggest PAK1 as a potential molecular target for the restoration of β-cell mass.
糖尿病患者功能性β细胞数量不足是由于β细胞死亡和复制失衡，以及 2 型糖尿病供体胰岛中 PAK1 蛋白水平降低所致。这表明 PAK1 在维持β细胞数量方面可能起作用。在这里，我们旨在研究 PAK1 与 Survivin 之间的联系，Survivin 是β细胞复制所必需的一种蛋白质。PAK1 敲除 (KO) 小鼠胰岛中 Survivin 蛋白表达降低。用 siRNA 介导的 PAK1 抑制 MIN6 β 细胞也降低了 Survivin 蛋白，并表现出泛素化 Survivin 水平增加。然而，在 PAK1 KO 小鼠胰岛和 PAK1 耗尽的 MIN6 β 细胞中并未发现 Survivin mRNA 有显著变化。高糖应激下 MIN6 细胞中 Survivin 水平的降低可通过表达外源性 PAK1 来预防。此外，过表达 Survivin 恢复了由 PAK1 缺失引起的β细胞增殖受损。这些数据表明 PAK1 在调节β细胞中 Survivin 蛋白稳定性方面起作用，并表明 PAK1 是恢复β细胞数量的潜在分子靶标。
