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-kappab的作用，NF-kappab是一种与细胞存活有关的无处不在的蛋白质，在乙醇作用中。首先，我总结了乙醇与先前报告的NF-kappab激活之间的关系和乙醇的药代动力学。在这些基础上，我们检查了乙醇的NF-kappab的激活机制。结果总结如下1。急性乙醇敏化的NF-kappab和诱导凋亡蛋白抑制剂（IAP）。 Mg135（一种蛋白酶体抑制剂MG135）降低了乙醇诱导的NF-kappab激活和IAP表达。随着蛋白酶体抑制剂增加NF-kappab，JNK-AP-1途径（一种细胞死亡信号传导）被激活。这些发现表明，乙醇诱导的NF-kappab激活调节JNK-AP-1途径通过调节IAPs.2。急性乙醇在抑制ADH下诱导的JNK和AKT激活，JNK的激活被抗氧化剂降低。 Akt与JIP1的结合是活性的，而JNK与JIP1的结合是无效的。3。乙醇通过使用几个基因甲状腺元素在IGF受体和FOXO之间作用任何途径，从而降低了C.Elegans的寿命4。乙醇通过TLR4信号传导激活NF-kappab。乙醇和LPS的CO处理累积了NF-kappab激活，以诱导促炎性细胞因子，即TNF-Alpha，IL-1Beta，IL-10，IL-10等。5。