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Molecular mechanisms of inhibition of ubiquitination by alcohol

酒精抑制泛素化的分子机制

基本信息

批准号：
14570393
负责人：
MATSUMOTO Hiroshi
金额：
$ 2.24万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570393/
关键词：
Alcohol NF-kappaB IAP JNK Akt TLR4 cell survival エタノールユビキチネーション転写制御因子脂肪肝 PPAR NF-κB IκB LPS

项目摘要

The aim in the present study was to clarify role of NF-kappaB, a ubiquitous protein related to cell survival, in ethanol action. First, I summarized relationship between ethanol and activation of NF-kappaB by previous reports and pharmacokinetics of ethanol. On these bases, we examined the activation mechanisms of NF-kappaB by ethanol. The results summarize as follows.1. Acute ethanol acitivated NF-kappaB and induces inhibitor of apoptosis proteins (IAPs). NF-kappaB activation and IAP expression induced by ethanol were decreased by MG135, a proteasome inhibitor. As NF-kappaB was increased by the proteasome inhibitor, JNK-AP-1 pathway, a cell death signaling, was activated. These findings suggest that ethanol-induced NF-kappaB activation regulates JNK-AP-1 pathway related to cell death by regulation of IAPs.2. Acute ethanol induced activation of JNK and Akt under inhibition of ADH, and activation of JNK was reduced by an antioxidant. Akt binding to JIP1 was active, while JNK binding to JIP1 was inactive.3. Ethanol acted any pathways between IGF receptor and FOXO by using several knockout C.elegans, which reduced life span in C.elegans.4. Ethanol activated NF-kappaB via TLR4- signaling. Co treatment with ethanol and LPS accumulated NF-kappaB activation to induce proinflammatory cytokines, i.e. TNF-alpha, IL-1beta, IL-10 and so on.5.

本研究的目的是阐明NF-κ B（一种与细胞生存相关的普遍存在的蛋白质）在乙醇作用中的作用。本文首先通过文献报道和乙醇的药代动力学，总结了乙醇与NF-κ B活化的关系。在此基础上，我们研究了乙醇对NF-κ B的激活机制。研究结果如下：1.急性乙醇激活NF-κ B并诱导凋亡抑制蛋白（IAP）。蛋白酶体抑制剂MG 135可降低乙醇诱导的NF-κ B活化和IAP表达。随着蛋白酶体抑制剂增加NF-κ B，JNK-AP-1途径（细胞死亡信号传导）被激活。这些结果表明，乙醇诱导的NF-κ B活化通过调节IAP来调节与细胞死亡相关的JNK-AP-1通路.急性乙醇诱导激活JNK和Akt的抑制下ADH，和JNK的激活减少了抗氧化剂。Akt与JIP 1的结合是活跃的，而JNK与JIP 1的结合是不活跃的.乙醇通过几种敲除线虫作用于IGF受体和FOXO之间的任何通路，降低线虫的寿命.乙醇通过TLR 4信号传导激活NF-κ B。乙醇和LPS联合处理可激活NF-κ B，诱导TNF-α、IL-1 β、IL-10等促炎细胞因子的产生.