The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic β cells
The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic β cells
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DOI：
10.1242/jcs.00356
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发表时间：
2003-04-15
影响因子：
4
通讯作者：
Waeber, G
中科院分区：
文献类型：
--
作者：
Haefliger, JA;Tawadros, T;Waeber, G
在胰岛素分泌细胞中，细胞因子激活c-jun氨基末端激酶(JNK)，这有助于细胞向凋亡发出信号。JNK的激活需要小鼠JNK相互作用蛋白1(JIP-1)或人胰岛脑1(IB1)的存在，后者组织MLK3、MKK7和JNK以实现适当的信号特异性。在这里，我们使用腺病毒介导的基因转移来调节IB1/JIP-1的细胞含量，以探讨IB1/JIP-1对β细胞存活的贡献。胰岛素分泌细胞系INS-1或分离的大鼠胰岛暴露于细胞因子(干扰素-γ、肿瘤坏死因子-a和白介素1-β)后，IB1/JIP-1含量显著降低，JNK活性和凋亡率增加。在INS-1细胞中，过量生产IB1/JIP-1可以阻止JNK诱导的这种促凋亡程序，这种作用与抑制caspase-3的切割有关。相反，减少INS-1细胞和分离的胰岛中IB1/JIP-1的含量会导致基础细胞和细胞因子刺激的细胞凋亡显著增加。在携带IB1/JIP-1基因选择性中断的杂合子小鼠中，单倍体不足的单独胰岛中IB1/JIP-1含量的减少与JNK活性和基础细胞凋亡的增加有关。这些数据表明，β细胞中IB1-JIP-1含量的调节是JNK信号通路和细胞因子诱导的细胞凋亡的关键调节因子。
In insulin-secreting cells, cytokines activate the c-Jun N-terminal kinase (JNK), which contributes to a cell signaling towards apoptosis. The JNK activation requires the presence of the murine scaffold protein JNK-interacting protein 1 (JIP-1) or human Islet-brain 1(IB1), which organizes MLK3, MKK7 and JNK for proper signaling specificity. Here, we used adenovirus-mediated gene transfer to modulate IB1/JIP-1 cellular content in order to investigate the contribution of IB1/JIP-1 to beta-cell survival. Exposure of the insulin-producing cell line INS-1 or isolated rat pancreatic islets to cytokines (interferon-gamma, tumor necrosis factor-a and interieukin-1beta) induced a marked reduction of IB1/JIP-1 content and a concomitant increase in JNK activity and apoptosis rate. This JNK-induced pro-apoptotic program was prevented in INS-1 cells by overproducing IB1/JIP-1 and this effect was associated with inhibition of caspase-3 cleavage. Conversely, reducing IB1/JIP-1 content in INS-1 cells and isolated pancreatic islets induced a robust increase in basal and cytokine-stimulated apoptosis. In heterozygous mice carrying a selective disruption of the IB1/JIP-1 gene, the reduction in IB1/JIP-1 content in happloinsufficient isolated pancreatic islets was associated with an increased JNK activity and basal apoptosis. These data demonstrate that modulation of the IB1-JIP-1 content in beta cells is a crucial regulator of JNK signaling pathway and of cytokine-induced apoptosis.