C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2.
C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2.
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DOI：
10.1371/journal.pone.0097694
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Clare-Salzler MJ
中科院分区：
文献类型：
--
作者：
Xia CQ;Zhang P;Li S;Yuan L;Xia T;Xie C;Clare-Salzler MJ
慢性粒细胞白血病患者接受酪氨酸激酶抑制剂伊马替尼治疗后，血清 C 肽水平升高。伊马替尼特异性抑制酪氨酸激酶 c-Abl。然而，伊马替尼治疗如何导致胰岛素水平升高的机制尚不清楚。具体来说，关于伊马替尼是否直接影响β细胞促进胰岛素产生的研究很少。在这项研究中，我们发现伊马替尼显着诱导葡萄糖刺激的β细胞和静息β细胞中的胰岛素表达。与这一发现一致，siRNA 敲低 c-Abl 和 c-Abl 过表达分别显着增强和抑制 β 细胞中的胰岛素表达。出乎意料的是，高浓度的葡萄糖显着诱导c-Abl表达，表明c-Abl可能在葡萄糖刺激期间平衡胰岛素产生中发挥作用。进一步的研究表明，c-Abl 抑制不会影响主要胰岛素基因转录因子、胰腺和十二指肠同源盒-1 (PDX-1) 的表达。有趣的是，抑制c-Abl会增强NKx2.2，而β细胞中c-Abl的过度表达会显着下调NKx2.2，而NKx2.2是胰岛素基因表达的正调节因子。此外，我们发现 c-Abl 抑制显着增强了 β 细胞上葡萄糖转运蛋白 GLUT2 的表达。我们的研究证明了一种以前未被认识的机制，该机制通过 c-Abl 调节的 NKx2.2 和 GLUT2 控制胰岛素表达。治疗性靶向β细胞c-Abl可用于治疗糖尿病或β细胞肿瘤、胰岛素瘤。
Chronic myelogenous leukemia patients treated with tyrosine kinase inhibitor, Imatinib, were shown to have increased serum levels of C-peptide. Imatinib specifically inhibits the tyrosine kinase, c-Abl. However, the mechanism of how Imatinib treatment can lead to increased insulin level is unclear. Specifically, there is little investigation into whether Imatinib directly affects β cells to promote insulin production. In this study, we showed that Imatinib significantly induced insulin expression in both glucose-stimulated and resting β cells. In line with this finding, c-Abl knockdown by siRNA and overexpression of c-Abl markedly enhanced and inhibited insulin expression in β cells, respectively. Unexpectedly, high concentrations of glucose significantly induced c-Abl expression, suggesting c-Abl may play a role in balancing insulin production during glucose stimulation. Further studies demonstrated that c-Abl inhibition did not affect the major insulin gene transcription factor, pancreatic and duodenal homeobox-1 (PDX-1) expression. Of interest, inhibition of c-Abl enhanced NKx2.2 and overexpression of c-Abl in β cells markedly down-regulated NKx2.2, which is a positive regulator for insulin gene expression. Additionally, we found that c-Abl inhibition significantly enhanced the expression of glucose transporter GLUT2 on β cells. Our study demonstrates a previously unrecognized mechanism that controls insulin expression through c-Abl-regulated NKx2.2 and GLUT2. Therapeutic targeting β cell c-Abl could be employed in the treatment of diabetes or β cell tumor, insulinoma.
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蛋白质结合阵列数据的新计算分析确定了胰腺中NKX2.2的直接靶标。
影响因子：
3
作者：
Hill JT;Anderson KR;Mastracci TL;Kaestner KH;Sussel L
通讯作者：
Sussel L
影响因子：
6
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Welsh, Nils
DOI：
10.1006/bbrc.1996.1875
发表时间：
1996-12-24
影响因子：
3.1
作者：
Watada, H;Kajimoto, Y;Yamasaki, Y
通讯作者：
Yamasaki, Y
影响因子：
10.9
作者：
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通讯作者：
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