The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes
The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes
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DOI：
10.1111/j.1432-1033.1997.0240a.x
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发表时间：
1997-01-15
期刊：
影响因子：
--
通讯作者：
Meijer, AJ
中科院分区：
文献类型：
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作者：
Blommaart, EFC;Krause, U;Meijer, AJ
最近的研究表明，磷脂酰肌醇3-激酶是必不可少的，在许多过程的调节依赖于膜流动。自噬是一个复杂的途径，其中细胞物质，包括蛋白质，可以降解。膜流在这一过程中起着关键作用。为了发现磷脂酰肌醇3-激酶是否也是自噬所必需的，我们测试了两种结构无关的磷脂酰肌醇3-激酶抑制剂渥曼青霉素和2-（4-吗啉基）-8-苯基色酮（LY 294002）对自噬的影响。渥曼青霉素（IC 50 30 nM）和LY 294002（IC 50 10 μ M）的抗蛋白水解作用伴随着自噬螯合的抑制，而不是溶酶体pH值的增加或细胞内ATP的减少。没有进一步的抑制蛋白水解的两种化合物时，观察到自噬已被最大限度地抑制高浓度的氨基酸。3-甲基腺嘌呤，这是常用的自噬螯合的特异性抑制剂，是磷脂酰肌醇3-激酶的抑制剂，从而提供了一个目标，其action.It建议，磷脂酰肌醇3-激酶活性是自噬所需的。3-甲基腺嘌呤通过抑制这种酶来抑制自噬。
Recent studies indicate that phosphatidylinositol 3-kinase is essential in the regulation of many processes dependent on membrane flow. Autophagy is a complex pathway in which cell material, including proteins, can be degraded. Membrane flow plays a pivotal role in this process. To find out whether phosphatidylinositol 3-kinase is also required for autophagy, we tested the effects on autophagy of two structurally unrelated phosphatidylinositol 3-kinase inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenylchromone (LY294002).The addition of low concentrations of each of these inhibitors to incubations of hepatocytes in the absence of amino acids resulted in a strong inhibition of proteolysis. The antiproteolytic effect of wortmannin (IC50 30 nM) and LY294002 (IC50 10 mu M) was accompanied by inhibition of autophagic sequestration and not by an increase in lysosomal pH or a decrease in intracellular ATP. No further inhibition of proteolysis by the two compounds was observed when autophagy was already maximally inhibited by high concentrations of amino acids.3-Methyladenine, which is commonly used as a specific inhibitor of autophagic sequestration, was an inhibitor of phosphatidylinositol 3-kinase, thus providing a target for its action.It is proposed that phosphatidylinositol 3-kinase activity is required for autophagy. 3-Methyladenine inhibits autophagy by inhibition of this enzyme.