EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells.
EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells.
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DOI：
10.1186/1471-2199-11-66
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发表时间：
2010-08-31
影响因子：
--
通讯作者：
Altura RA
中科院分区：
文献类型：
--
作者：
Wang H;Gambosova K;Cooper ZA;Holloway MP;Kassai A;Izquierdo D;Cleveland K;Boney CM;Altura RA
出生后胰岛β细胞群的扩张是维持葡萄糖稳态所必需的。这种β细胞的扩增受多种生长因子的调控，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）。这些丝裂原通过AKT、ERK、STAT3和JNK等下游信号通路调控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癌胎儿蛋白，是癌细胞中已知的IGF-1和EGF的转录靶点。在此，我们分析了β细胞分裂原IGF-1和EGF在已建立的胰腺β细胞模型细胞系MIN6和INS-1以及原代小鼠胰岛中对survivin调控的影响。在胰腺β细胞中，葡萄糖、胰岛素或EGF治疗在早期时间点增加了survivin蛋白水平。相比之下，IGF-1治疗对存活素没有显著影响。在Raf-1/MEK/ERK通路的下游抑制剂存在的情况下，egf刺激的survivin蛋白增加被消除。EGF对survivin转录无显著影响，但通过抑制survivin泛素化，延长了survivin蛋白的半衰期，稳定了survivin蛋白的水平。本研究通过延长survivin蛋白半衰期和抑制泛素介导的蛋白酶体降解途径，确定了EGF在胰腺β细胞中通过Raf-1/MEK/ERK通路调控survivin的新机制。这一机制可能对出生后调节β细胞扩增具有重要意义。
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.
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