cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets.
cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets.
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DOI：
10.1007/s00125-011-2338-7
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发表时间：
2012-01
期刊：
影响因子：
8.2
通讯作者：
Kahn, S. E.
中科院分区：
文献类型：
--
作者：
Subramanian, S. L.;Hull, R. L.;Zraika, S.;Aston-Mourney, K.;Udayasankar, J.;Kahn, S. E.
人胰岛淀粉样多肽(HIAPP)聚集为胰岛淀粉样蛋白与2型糖尿病患者β细胞凋亡增加和β细胞质量减少有关。胰岛淀粉样蛋白的形成诱导氧化应激，从而促进β细胞的凋亡。CJUN氨基末端激酶(JNK)通路是包括氧化应激和外源性hIAPP在内的应激刺激引起的β细胞凋亡的重要调节因子。我们确定了内源性hIAPP形成的淀粉样蛋白是否通过JNK激活和下游信号通路介导了β细胞的凋亡。HIAPP转基因和非转基因小鼠胰岛在16.7 mmol/L葡萄糖中培养144h以诱导胰岛淀粉样蛋白的存在或不存在淀粉样蛋白抑制剂刚果红或细胞通透性JNK抑制剂。检测了内源性和外源性凋亡途径中的淀粉样蛋白、β细胞凋亡、JNK信号和下游靶标的激活情况。在培养48h和144h后，转hIAPP基因的胰岛出现JNK活化，并形成胰岛淀粉样蛋白。无论是高糖还是hIAPP转基因都不足以激活独立于胰岛淀粉样蛋白的JNK。刚果红抑制胰岛淀粉样蛋白的形成减少了β细胞的凋亡，并部分降低了JNK的活性。JNK抑制剂处理减少了β细胞的凋亡，而不影响胰岛淀粉样蛋白。胰岛淀粉样蛋白以JNK依赖的方式增加外源性(Fas，FAdd)和内在(Bim[也称为Bcl2l11])凋亡途径的标志物caspase3和抗凋亡分子Bclx1(也称为Bcl2l1)的mRNA水平。胰岛淀粉样蛋白的形成诱导JNK激活，在外在和内在途径中主要上调促凋亡信号，导致β细胞凋亡。
Aggregation of human islet amyloid polypeptide (hIAPP) as islet amyloid is associated with increased beta cell apoptosis and reduced beta cell mass in type 2 diabetes. Islet amyloid formation induces oxidative stress, which contributes to beta cell apoptosis. The cJUN N-terminal kinase (JNK) pathway is a critical mediator of beta cell apoptosis in response to stress stimuli including oxidative stress and exogenous application of hIAPP. We determined whether amyloid formation by endogenous hIAPP mediates beta cell apoptosis through JNK activation and downstream signalling pathways. hIAPP transgenic and non-transgenic mouse islets were cultured for up to 144 h in 16.7 mmol/l glucose to induce islet amyloid in the presence or absence of the amyloid inhibitor Congo Red or a cell-permeable JNK inhibitor. Amyloid, beta cell apoptosis, JNK signalling and activation of downstream targets in the intrinsic and extrinsic apoptotic pathways were measured. JNK activation occurred with islet amyloid formation in hIAPP transgenic islets after 48 and 144 h in culture. Neither high glucose nor the hIAPP transgene alone was sufficient to activate JNK independent of islet amyloid. Inhibition of islet amyloid formation with Congo Red reduced beta cell apoptosis and partially decreased JNK activation. JNK inhibitor treatment reduced beta cell apoptosis without affecting islet amyloid. Islet amyloid increased mRNA levels of markers of the extrinsic (Fas, Fadd) and intrinsic (Bim [also known as Bcl2l11]) apoptotic pathways, caspase 3 and the anti-apoptotic molecule Bclxl (also known as Bcl2l1) in a JNK-dependent manner. Islet amyloid formation induces JNK activation, which upregulates predominantly pro-apoptotic signals in both extrinsic and intrinsic pathways, resulting in beta cell apoptosis.
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DOI：
10.1016/j.biocel.2009.01.002
发表时间：
2009-07-01
影响因子：
4
作者：
Li, Xiao-Ling;Xu, Gang;Chan, Juliana C. N.
通讯作者：
Chan, Juliana C. N.
影响因子：
7.7
作者：
DALESSIO, DA;VERCHERE, CB;ENSINCK, JW
通讯作者：
ENSINCK, JW
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
7.7
作者：
Huang, Chang-jiang;Lin, Chia-yu;Butler, Peter C.
通讯作者：
Butler, Peter C.
DOI：
10.1073/pnas.84.23.8628
发表时间：
1987-12-01
影响因子：
11.1
作者：
COOPER, GJS;WILLIS, AC;REID, KBM
通讯作者：
REID, KBM