Department of Hepatopancreatobiliary Surgery, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun 130021, China.
Biochem Biophys Res Commun. 2012 Feb 10;418(2):433-8. doi: 10.1016/j.bbrc.2012.01.056. Epub 2012 Jan 20.
A20 was initially identified as a primary gene product following TNF α treatment in human umbilical vein endothelial cells. Increased A20 expression is associated with tumorigenesis in many cancers, whereas the loss of A20 function is linked to lymphoma. It has been reported that A20 protects cells from TRAIL-induced apoptosis; however, the mechanism by which A20 is involved is still largely unknown. Our results indicate that TRAIL induces the hepatocellular carcinoma apoptosis associated with A20 knockdown in a concentration-dependent manner. TRAIL-induced apoptosis requires p18 caspase-8 activation, and, the activation of caspase-8 is at least in part, due to the direct cleavage of RIP1 by A20 knockdown. These findings suggest that A20 modulates the sensitivity to TRAIL by RIP1 ubiquitination, thereby repressing the recruitment and activation of pro-caspase-8 into the active form caspase-8. Thus, our study suggests that A20 protects against TRAIL-induced apoptosis through the regulation of RIP1 ubiquitination.
A20 最初在人脐静脉内皮细胞经 TNFα 处理后被鉴定为主要基因产物。A20 的表达增加与许多癌症的肿瘤发生有关，而 A20 功能的丧失与淋巴瘤有关。据报道，A20 可保护细胞免受 TRAIL 诱导的凋亡；然而，A20 参与的机制在很大程度上仍不清楚。我们的结果表明，TRAIL 以浓度依赖的方式诱导与 A20 敲低相关的肝癌细胞凋亡。TRAIL 诱导的细胞凋亡需要 p18 caspase-8 的激活，而 caspase-8 的激活至少部分是由于 RIP1 被 A20 敲低直接切割。这些发现表明，A20 通过 RIP1 的泛素化来调节对 TRAIL 的敏感性，从而抑制前半胱天冬酶-8 募集和激活为活性形式的半胱天冬酶-8。因此，我们的研究表明，A20 通过调节 RIP1 的泛素化来防止 TRAIL 诱导的细胞凋亡。
