The role of death effector domain-containing proteins in acute oxidative cell injury in hepatocytes.
The role of death effector domain-containing proteins in acute oxidative cell injury in hepatocytes.
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含死亡效应结构域的蛋白质在肝细胞急性氧化细胞损伤中的作用。
DOI：
10.1016/j.freeradbiomed.2012.02.049
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发表时间：
2012
影响因子：
7.4
通讯作者：
Schuchmann,Marcus
中科院分区：
文献类型：
--
作者：
Schattenberg,JörnM;Wörns,MarcusA;Zimmermann,Tim;He,You-Wen;Galle,PeterR;Schuchmann,Marcus
细胞凋亡是一种调节肝组织稳态的机制，并有助于肝脏疾病的急性和慢性损伤。凋亡信号级联涉及死亡诱导信号复合物（DISC）的激活和随后含有死亡效应结构域（DED）的蛋白质的募集，其调节下游效应分子。其中突出的是Fas相关死亡结构域（FADD）和细胞半胱天冬酶8样抑制蛋白（cFLIP），这些蛋白质的改变可导致生理过程的严重破坏，包括急性肝衰竭或肝细胞癌。它们在独立于DISC的细胞信号传导事件中的作用仍然不确定。氧化应激可通过直接作用于分子或通过激活细胞内信号传导途径（包括促分裂原活化蛋白激酶（MAPK））而引起细胞损伤。在这种情况下，cJun N-末端激酶（JNK）/AP-1/cJun信号通路的长期激活促进肝细胞凋亡，而细胞外信号调节激酶（Erk）的激活发挥保护作用。我们研究了FADD和cFLIP在肝细胞中由超氧化物发生剂甲萘醌诱导的急性氧化应激中的作用。甲萘醌导致剂量依赖性的主要是坏死性细胞死亡。表达截短的显性阴性FADD蛋白的肝细胞受到部分保护，而cFLIP缺陷肝细胞显示甲萘醌引起的细胞死亡增加。同时，Erk磷酸化在表达dnFADD的肝细胞中增强，而在cFLIP缺陷肝细胞中降低。肝细胞损伤伴随着促凋亡因子的释放增加和JNK/cJun活化增加。因此，FADD和cFLIP有助于调节肝细胞中急性氧化应激引起的细胞死亡，涉及MAPK信号传导。这意味着DED蛋白参与细胞存活的调节，超出了它们在细胞死亡受体-配体介导的细胞凋亡中的作用。
Apoptosis is a mechanism that regulates hepatic tissue homeostasis and contributes to both acute and chronic injury in liver disease. The apoptotic signaling cascade involves activation of the death-inducing signaling complex (DISC) and subsequent recruitment of proteins containing death effector domains (DED), which regulate downstream effector molecules. Prominent among these are the Fas-associated death domain (FADD) and the cellular caspase 8-like inhibitory protein (cFLIP), and alterations in these proteins can lead to severe disruption of physiological processes, including acute liver failure or hepatocellular carcinoma. Their role in cell signaling events independent of the DISC remains undetermined. Oxidative stress can cause cell injury from direct effects on molecules or by activating intracellular signaling pathways including the mitogen-activated protein kinases (MAPKs). In this context, prolonged activation of the cJun N-terminal kinase (JNK)/AP-1/cJun signaling pathway promotes hepatocellular apoptosis, whereas activation of the extracellular signal-regulated kinase (Erk) exerts protection. We investigated the roles of FADD and cFLIP in acute oxidant stress induced by the superoxide generator menadione in hepatocytes. Menadione resulted in dose-dependent predominantly necrotic cell death. Hepatocytes expressing a truncated, dominant-negative FADD protein were partially protected, whereas cFLIP-deficient hepatocytes displayed increased cell death from menadione. In parallel, Erk phosphorylation was enhanced in hepatocytes expressing dnFADD and decreased in cFLIP-deficient hepatocytes. Hepatocyte injury was accompanied by increased release of proapoptotic factors and increased JNK/cJun activation. Thus, FADD and cFLIP contribute to the regulation of cell death from acute oxidant stress in hepatocytes involving MAPK signaling. This implies that DED-containing proteins are involved in the regulation of cellular survival beyond their role in cell death receptor–ligand-mediated apoptosis.
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通过急性脑内输注两种四氢异喹啉和一种β-咔啉诱导大鼠饮酒。
影响因子：
4.2
作者：
R. D. Myers;M. Oblinger
通讯作者：
M. Oblinger
多重代谢理论、饮酒和产醇基因。
DOI：
--
发表时间：
1985
期刊：
Progress in clinical and biological research
影响因子：
--
作者：
Myers,RD
通讯作者：
Myers,RD
将四氢罂粟碱 (THP) 注入脑室诱导猴子饮酒
DOI：
--
发表时间：
1982
期刊：
Pharmacology, Biochemistry and Behavior
影响因子：
--
作者：
R. D. Myers;M. McCaleb;W. Ruwe
通讯作者：
W. Ruwe
对大鼠苯二氮卓受体具有激动和反激动特性的 β-咔啉
影响因子：
2.5
作者：
D. Stephens;W. Kehr;H. Schneider;R. Schmiechen
通讯作者：
R. Schmiechen
大鼠饮酒：四氢-β-咔啉脑室内治疗后饮酒量增加
DOI：
--
发表时间：
1982
期刊：
Pharmacology, Biochemistry and Behavior
影响因子：
--
作者：
L. Tuomisto;M. Airaksinen;P. Peura;C. Eriksson
通讯作者：
C. Eriksson