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首页> 外文期刊>BMC Molecular Biology >EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells
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EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells

机译：EGF通过分泌胰岛素的胰腺β细胞中的Raf-1 / ERK途径调节survivin的稳定性

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Postnatal expansion of the pancreatic β-cell mass is required to maintain glucose homeostasis immediately after birth. This β-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of β-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the β-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic β-cell model cell lines, MIN6 and INS-1 and in primary mouse islets. In pancreatic β-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination. This study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic β-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating β-cell expansion after birth.
机译：出生后需要胰岛β细胞团块的产后扩展来维持葡萄糖稳态。这种β细胞的扩张受到多种生长因子的调节，包括葡萄糖，胰岛素，胰岛素样生长因子（IGF-1）和表皮生长因子（EGF）。这些有丝分裂原通过几个下游途径（AKT，ERK，STAT3和JNK）发出信号，以调节β细胞的存活和增殖。 Survivin是一种具有促增殖和抗凋亡特性的胎粪蛋白，是癌细胞中IGF-1和EGF的已知转录靶标。在这里，我们分析了已建立的胰腺β细胞模型细胞系MIN6和INS-1以及原代小鼠胰岛中β细胞促分裂原IGF-1和EGF对survivin调节的影响。在胰腺β细胞中，在早期时间点用葡萄糖，胰岛素或EGF治疗可增加survivin蛋白水平。相比之下，IGF-1治疗后未观察到对生存素的显着影响。在存在Raf-1 / MEK / ERK途径的下游抑制剂的情况下，EGF刺激的survivin蛋白增加被消除。 EGF对存活蛋白的转录没有明显影响，但是它通过抑制存活的泛素化来延长存活蛋白的半衰期并稳定了存活蛋白的水平。这项研究通过延长survivin蛋白半衰期并抑制泛素介导的蛋白酶体降解途径，定义了EGF通过Raf-1 / MEK / ERK途径在胰腺β细胞中调节survivin的新机制。该机制对于调节出生后β细胞的膨胀可能很重要。

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