Tip60-FOXO调节果蝇JNK信号通路介导的细胞凋亡  

Tip60-FOXO regulates JNK signaling mediated apoptosis in Drosophila

作　　者：杨剑 石国娟 彭昂惠 徐清波 王睿琪 薛雷 喻昕阳 孙艺昊 Jian Yang;Guojuan Shi;Anghui Peng;Qingbo Xu;Ruiqi Wang;Lei Xue;Xinyang Yu;Yihao Sun(Molecular Genetics Team of the Institute of Translational Medicine,Zhuhai People’s Hospital(Zhuhai Clinical Medical College of Jinan University),Zhuhai 519000,China)

机构地区：[1]珠海市人民医院(暨南大学珠海临床医学院)转化医学研究院分子遗传学团队,珠海519000

出　　处：《遗传》2024年第6期490-501,共12页Hereditas（Beijing)

基　　金：国家自然科学基金项目(编号:32100561,32100447);珠海市人民医院临床科研提升计划项目(编号:2023LCTS-36,2023LCTS-41)资助。

摘　　要：JNK信号通路参与并调控了一系列重要的生理活动,包括细胞增殖、分化、迁移、凋亡及应激反应等,其失调与发育缺陷和肿瘤等多种重大疾病的发生与发展密切相关。筛选鉴定JNK信号通路的新成员,丰富完善该通路网络,对预防和治疗相关癌症具有重要的科学意义和临床价值。本研究利用模式动物果蝇(Drosophila),结合遗传学、发育生物学、生物化学和分子生物学等手段,探究了Tip60与JNK信号通路的互作关系,并揭示了其调控机制。结果表明,Tip60的乙酰基转移酶功能缺失导致JNK信号通路激活,并能诱发JNK依赖的细胞凋亡;遗传上位性分析实验表明,Tip60作用于JNK蛋白的下游,与转录因子FOXO平行;生化结果证明Tip60可以结合FOXO,并将其乙酰化。在果蝇中引入人Tip60,发现其能够很好地挽救果蝇JNK信号激活造成的细胞凋亡表型,证明Tip60对JNK信号的调控从果蝇到人高度保守。本研究进一步完善了JNK信号网络,揭示了Tip60在JNK依赖的细胞凋亡中的作用及机制,为相关癌症的预防和治疗提供了新的思路和潜在的药物靶点。The JNK signaling pathway plays crucial roles in various physiological processes,including cell proliferation,differentiation,migration,apoptosis,and stress response.Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases,such as developmental defects and tumors.Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers.This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics,developmental biology,biochemistry,and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway,and elucidated its regulatory mechanisms.Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis.Genetic epistasis analysis reveals that Tip60 acts downstream of JNK,paralleling with the transcription factor FOXO.The biochemical results confirm that Tip60 can bind to FOXO and acetylate it.Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation,underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans.This study further enhances our understanding of the regulatory network of the JNK signaling pathway.By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis,it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.

关 键 词：黑腹果蝇 JNK信号通路 细胞凋亡 Tip60 

分 类 号：R730.2[医药卫生—肿瘤]