军事医学2017，Vol.41Issue(11)：887-893,928,8.DOI:10.7644/j.issn.1674-9960.2017.11.005
PI3K调控细胞程序性坏死的分子机制
Identification of molecular mechanism of necroptosis mediated by PI3K
摘要
Abstract
Objective To identify the molecular mechanism of phosphatidylinositol-3-kinase (PI3K) in mediating necroptosis induced by tumor necrosis factor alpha (TNFα).Methods RNA interference mediated by lentivirus short hairpin RNA(shRNA) was used to downregulate p110α in L929 cells and Western blotting was used to determine the knockdown efficiency.In addition,Western blotting was used to detect the phosphorylation level of RIP1,RIP3 and MLKL in L929 cells treated with or without TNFα plus Z-VAD.Duolink assay kit was used to detect the interactions between different proteins or the same proteins.Results p110α knockdown was efficiently mediated by the lentivirus shRNA,which significantly suppressed the phosphorylation of RIP1,RIP3 and MLKL in the absence or presence of TNFα plus Z-VAD stimulation.Moreover,the interactions between p110α and RIP3,but not RIP1,increased in a time-dependent manner during the process of necroptosis,and p110α knockdown significantly inhibited the formation of necrosome and RIP1 homodimer or RIP3 homodimer.Conclusion PI3K mediates the TNFα-induced necroptosis by promoting the activation of RIP1/RIP3/MLKL signaling pathway.Given the increasing direct interactions between p110α and RIP3 during the process of necrosome formation,PI3K may regulate RIP3 kinase activity via direct phosphorylation of RIP3.关键词
磷脂酰肌醇3-激酶/肿瘤坏死因子α/细胞程序性坏死/受体相互作用蛋白Key words
phosphatidylinositol-3-kinase/tumor necrosis factor alpha/necroptosis/receptor-interacting protein分类
医药卫生引用本文复制引用
胡世平,王籽橙,陈国柱,于继云..PI3K调控细胞程序性坏死的分子机制[J].军事医学,2017,41(11):887-893,928,8.基金项目
国家自然科学基金资助项目(31201041) （31201041）
国家重大科技专项重大新药创制资助项目(2014ZX09304313-003) （2014ZX09304313-003）
