AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase
AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase
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DOI：
10.1677/jme.0.0300151
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发表时间：
2003-04-01
影响因子：
3.5
通讯作者：
Van de Casteele, M
中科院分区：
文献类型：
--
作者：
Kefas, BA;Cai, Y;Van de Casteele, M
我们最近发现，已知在原代 β 细胞中激活 AMP 激活蛋白激酶 (AMPK) 的条件可以触发其凋亡。本研究表明，MIN6 β 细胞系也是如此，该细胞系被用来研究潜在的机制。 AMPK 的持续激活是通过与腺苷类似物 AICA-核苷一起培养或在低葡萄糖浓度下诱导的。两种条件均诱导 AMPK、c-Jun-N 末端激酶 (JNK) 和 caspase-3 依次激活。 AMPK 对 JNK 激活和凋亡的影响通过组成型活性 AMPK 的腺病毒表达得到证实，这种情况再现了先前描述的 AMPK 依赖性对丙酮酸激酶和乙酰辅酶A-羧化酶的影响。 JNK 激活对细胞凋亡的影响通过以下观察得到证实：(i) 双香豆素的抑制作用可防止 caspase-3 激活和细胞凋亡，(ii) JNK 相互作用支架蛋白 JIP-1/IB-1 的腺病毒表达增加 AICA 核苷诱导的 JNK 激活和细胞凋亡。在原代 β 细胞中，AMPK 激活也被发现可以激活 JNK，主要涉及 JNK 2 (p54) 同工型。结论是，长时间刺激 AMPK 可以通过涉及 JNK 以及随后的 caspase-3 的激活途径诱导胰岛素生成细胞凋亡。
We have recently shown that conditions known to activate AMP-activated protein kinase (AMPK) in primary beta-cells can trigger their apoptosis. The present study demonstrates that this is also the case in the MIN6 beta-cell line, which was used to investigate the underlying mechanism. Sustained activation of AMPK was induced by culture with the adenosine analogue AICA-riboside or at low glucose concentrations. Both conditions induced a sequential activation of AMPK, c-Jun-N-terminal kinase (JNK) and caspase-3. The effects of AMPK on JNK activation and apoptosis were demonstrated by adenoviral expression of constitutively active AMPK, a condition which reproduced the earlier-described AMPK-dependent effects on pyruvate kinase and acetyl-coA-carboxylase. The effects of JNK activation on apoptosis were demonstrated by the observations that (i) its inhibition by dicumarol prevented caspase-3 activation and apoptosis, (ii) adenoviral expression of the JNK-interacting scaffold protein JIP-1/IB-1 increased AICA-riboside-induced JNK activation and apoptosis. In primary beta-cells, AMPK activation was also found to activate JNK, involving primarily the JNK 2 (p54) isoform. It is concluded that prolonged stimulation of AMPK can induce apoptosis of insulin-producing cells through an activation pathway that involves JNK, and subsequently, caspase-3.