Tip60-FOXO调节果蝇JNK信号通路介导的细胞凋亡【已撤稿】

doi:10.16288/j.yczz.24-105

遗传 ›› 2024, Vol. 46 ›› Issue (6): 490-501.doi: 10.16288/j.yczz.24-105

Tip60-FOXO调节果蝇JNK信号通路介导的细胞凋亡【已撤稿】

杨剑(), 石国娟(), 彭昂惠, 徐清波, 王睿琪, 薛雷, 喻昕阳(), 孙艺昊()

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

收稿日期:2024-04-17 修回日期:2024-05-06 出版日期:2024-06-20 发布日期:2024-05-24
通讯作者: 喻昕阳，博士，助理研究员，研究方向：三维基因组学。E-mail: xyu26@buffalo.edu;孙艺昊，博士，助理研究员，研究方向：果蝇分子遗传学。E-mail: sunyihao@ext.jnu.edu.cn
作者简介:杨剑，博士，主任医师，研究方向：肿瘤生物标记物。E-mail: 58202978@qq.com
石国娟，博士，主任医师，研究方向：肿瘤生物标记物。E-mail: xiaoyu.shitou@163.com
第一联系人：
杨剑和石国娟并列第一作者。
基金资助:
国家自然科学基金项目(32100561);国家自然科学基金项目(32100447);珠海市人民医院临床科研提升计划项目(2023LCTS-36);珠海市人民医院临床科研提升计划项目(2023LCTS-41)

Tip60-FOXO regulates JNK signaling mediated apoptosis in Drosophila

Yang Jian(), Shi Guojuan(), Peng Anghui, Xu Qingbo, Wang Ruiqi, Xue Lei, Yu Xinyang(), Sun Yihao()

Molecular Genetics Team of the Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China

Received:2024-04-17 Revised:2024-05-06 Published:2024-06-20 Online:2024-05-24
Supported by:
National Natural Science Foundation of China(32100561);National Natural Science Foundation of China(32100447);Clinical Research Promotion Project of Zhuhai People’s Hospital(2023LCTS-36);Clinical Research Promotion Project of Zhuhai People’s Hospital(2023LCTS-41)

摘要/Abstract

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。

关键词: 黑腹果蝇, JNK信号通路, 细胞凋亡, Tip60

Abstract:

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.

Key words: Drosophila melanogaster, JNK signaling pathway, apoptosis, Tip60

杨剑, 石国娟, 彭昂惠, 徐清波, 王睿琪, 薛雷, 喻昕阳, 孙艺昊. Tip60-FOXO调节果蝇JNK信号通路介导的细胞凋亡【已撤稿】[J]. 遗传, 2024, 46(6): 490-501.

Yang Jian, Shi Guojuan, Peng Anghui, Xu Qingbo, Wang Ruiqi, Xue Lei, Yu Xinyang, Sun Yihao. Tip60-FOXO regulates JNK signaling mediated apoptosis in Drosophila[J]. Hereditas(Beijing), 2024, 46(6): 490-501.

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参考文献 45

[1]	Chen WQ, Xia CF, Zheng RS, Zhou MG, Lin CQ, Zeng HM, Zhang SW, Wang LJ, Yang ZX, Sun KX, Li H, Brown MD, Islami F, Bray F, Jemal A, He J. Disparities by province, age, and sex in site-specific cancer burden attributable to 23 potentially modifiable risk factors in China: a comparative risk assessment. Lancet Glob Health, 2019, 7(2): e257-e269.
[2]	Chen WQ, Zheng RS, Baade PD, Zhang SW, Zeng HM, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
[3]	Labi V, Erlacher M. How cell death shapes cancer. Cell Death Dis, 2015, 6(3): e1675.
[4]	Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell, 2011, 147(2): 275-292. doi: 10.1016/j.cell.2011.09.024 pmid: 22000009
[5]	Dhanasekaran DN, Reddy EP. JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer, 2017, 8(9-10): 682-694.
[6]	Hu YM, Leo C, Yu S, Huang BCB, Wang H, Shen M, Luo Y, Daniel-Issakani S, Payan DG, Xu X. Identification and functional characterization of a novel human Misshapen/ Nck interacting kinase-related kinase, hMINKβ. J Biol Chem, 2004, 279(52): 54387-54397.
[7]	Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G. Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology, 1996, 216(2): 357-366. pmid: 8607265
[8]	Squatrito M, Gorrini C, Amati B. Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends Cell Biol, 2006, 16(9): 433-442. doi: 10.1016/j.tcb.2006.07.007 pmid: 16904321
[9]	Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell, 2000, 102(4): 463-473. pmid: 10966108
[10]	Doyon Y, Selleck W, Lane WS, Tan S, Côté J. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Mol Cell Biol, 2004, 24(5): 1884-1896. doi: 10.1128/MCB.24.5.1884-1896.2004 pmid: 14966270
[11]	Kusch T, Florens L, Macdonald WH, Swanson SK, Yates JR 3rd, Abmayr SM, Washburn MP, Workman JL. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science, 2004, 306(5704): 2084-2087. pmid: 15528408
[12]	Yamamoto T, Horikoshi M. Novel substrate specificity of the histone acetyltransferase activity of HIV-1-Tat interactive protein Tip60. J Biol Chem, 1997, 272(49): 30595-30598. doi: 10.1074/jbc.272.49.30595 pmid: 9388189
[13]	Patel JH, Du YP, Ard PG, Phillips C, Carella B, Chen CJ, Rakowski C, Chatterjee C, Lieberman PM, Lane WS, Blobel GA, Mcmahon SB. The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol Cell Biol, 2004, 24(24): 10826-10834. pmid: 15572685
[14]	Legube G, Linares LK, Tyteca S, Caron C, Scheffner M, Chevillard-Briet M, Trouche D. Role of the histone acetyl transferase Tip60 in the p53 pathway. J Biol Chem, 2004, 279(43): 44825-44833. doi: 10.1074/jbc.M407478200 pmid: 15310756
[15]	Sapountzi V, Logan IR, Robson CN. Cellular functions of TIP60. Int J Biochem Cell Biol, 2006, 38(9): 1496-1509.
[16]	Adamowicz M, Vermezovic J, D’Adda Di Fagagna F. NOTCH1 inhibits activation of ATM by impairing the formation of an ATM-FOXO3a-KAT5/Tip60 complex. Cell Rep, 2016, 16(8): 2068-2076. doi: S2211-1247(16)30956-1 pmid: 27524627
[17]	Khan C, Rusan NM. Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer. Trends Cancer, 2024, 10(4): 289-311.
[18]	Tsintzas E, Niccoli T. Using Drosophila amyloid toxicity models to study Alzheimer's disease. Ann Hum Genet, 2024.
[19]	Banerjee U, Girard JR, Goins LM, Spratford CM. Drosophila as a genetic model for hematopoiesis. Genetics, 2019, 211(2): 367-417. doi: 10.1534/genetics.118.300223 pmid: 30733377
[20]	Kahney EW, Snedeker JC, Chen X. Regulation of Drosophila germline stem cells. Curr Opin Cell Biol, 2019, 60: 27-35.
[21]	Enomoto M, Siow C, Igaki T. Drosophila as a cancer model. Adv Exp Med Biol, 2018, 1076: 173-194. doi: 10.1007/978-981-13-0529-0_10 pmid: 29951820
[22]	Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Cell Biol, 2007, 19(2): 142-149. doi: 10.1016/j.ceb.2007.02.001 pmid: 17303404
[23]	Gan T, Fan LX, Zhao L, Misra M, Liu M, Zhang M, Su Y. JNK signaling in Drosophila aging and longevity. Int J Mol Sci, 2021, 22(17): 9649.
[24]	Semba T, Sammons R, Wang XP, Xie XM, Dalby KN, Ueno NT. JNK signaling in stem cell self-renewal and differentiation. Int J Mol Sci, 2020, 21(7): 2613.
[25]	Rana A, Rana B, Mishra R, Sondarva G, Rangasamy V, Das S, Viswakarma N, Kanthasamy A. Mixed lineage kinase-c-Jun N-terminal kinase axis: a potential therapeutic target in cancer. Genes Cancer, 2013, 4(9-10): 334-341. doi: 10.1177/1947601913485415 pmid: 24349631
[26]	Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol Metab, 2017, 6(2): 174-184. doi: S2212-8778(16)30244-7 pmid: 28180059
[27]	Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Genet Dev, 2002, 12(1): 14-21. pmid: 11790549
[28]	Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M. The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO J, 1996, 15(22): 6269-6279. pmid: 8947050
[29]	Kockel L, Homsy JG, Bohmann D. Drosophila AP-1: lessons from an invertebrate. Oncogene, 2001, 20(19): 2347-2364. pmid: 11402332
[30]	Luo X, Puig O, Hyun J, Bohmann D, Jasper H. Foxo and Fos regulate the decision between cell death and survival in response to UV irradiation. EMBO J, 2007, 26(2): 380-390. pmid: 17183370
[31]	Uhlirova M, Bohmann D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J, 2006, 25(22): 5294-5304. doi: 10.1038/sj.emboj.7601401 pmid: 17082773
[32]	Essers MAG, Weijzen S, Saarloos I, de Ruiter ND, Bos JL, Burgering BMT. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J, 2004, 23(24): 4802-4812. doi: 10.1038/sj.emboj.7600476 pmid: 15538382
[33]	Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA, 2003, 100(5): 2432-2437. doi: 10.1073/pnas.0438011100 pmid: 12591950
[34]	Brown AK, Webb AE. Regulation of FOXO factors in mammalian cells. Curr Top Dev Biol, 2018, 127: 165-192. doi: S0070-2153(17)30055-8 pmid: 29433737
[35]	Snigdha K, Singh A, Kango-Singh M. Yorkie-Cactus (IkappaBalpha)-JNK axis promotes tumor growth and progression in Drosophila. Oncogene, 2021, 40(24): 4124-4136. doi: 10.1038/s41388-021-01831-4 pmid: 34017079
[36]	Lam D, Shah S, de Castro IP, Loh SHY, Martins LM. Drosophila happyhour modulates JNK-dependent apoptosis. Cell Death Dis, 2010, 1(8): e66.
[37]	Camilleri-Robles C, Serras F, Corominas M. Role of D-GADD45 in JNK-dependent apoptosis and regeneration in Drosophila. Genes(Basel), 2019, 10(5): 378.
[38]	Igaki T. Correcting developmental errors by apoptosis: lessons from Drosophila JNK signaling. Apoptosis, 2009, 14(8): 1021-1028.
[39]	Sun YL, Jiang XF, Price BD. Tip60: connecting chromatin to DNA damage signaling. Cell Cycle, 2014, 9(5): 930-936.
[40]	Tafesh-Edwards G, Eleftherianos I. JNK signaling in Drosophila immunity and homeostasis. Immunol Lett, 2020, 226: 7-11. doi: S0165-2478(20)30348-5 pmid: 32598968
[41]	Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: an emerging therapeutic target. Eur J Pharmacol, 2021, 901: 174079.
[42]	Saline M, Badertscher L, Wolter M, Lau R, Gunnarsson A, Jacso T, Norris T, Ottmann C, Snijder A. AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins. J Biol Chem, 2019, 294(35): 13106-13116. doi: 10.1074/jbc.RA119.008649 pmid: 31308176
[43]	Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. Biochim Biophys Acta, 2016, 1864(10): 1372-1401. doi: 10.1016/j.bbapap.2016.06.007 pmid: 27296530
[44]	Shen L, Lee S, Joo JC, Hong E, Cui ZY, Jo E, Park SJ, Jang HJ. Chelidonium majus induces apoptosis of human ovarian cancer cells via ATF3-mediated regulation of Foxo3a by Tip60. J Microbiol Biotechnol, 2022, 32(4): 493-503.
[45]	Tan KN, Avery VM, Carrasco-Pozo C. Metabolic roles of androgen receptor and Tip60 in androgen-dependent prostate cancer. Int J Mol Sci, 2020, 21(18): 6622.

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Tip60-FOXO调节果蝇JNK信号通路介导的细胞凋亡【已撤稿】

Tip60-FOXO regulates JNK signaling mediated apoptosis in Drosophila

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