USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia

查看全文 作　　者：Huizhuang [1]Shan;Xiangyun [1]Li;Xinhua [2]Xiao;Yuting [2]Dai;Jinyan [2]Huang;Junjun [3]Song;Meng [1]Liu;Li [1]Yang;Hu [1]Lei;Yin [4]Tong;Li [2]Zhou;Hanzhang [1]Xu;Yingli [1]Wu

机构地区：[1]Hongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;[2]Department of Hematology,Rui-Jin Hospital,Shanghai Jiao Tong University School of Medicine,No.197,Ruijin Er Road,Shanghai,China;[3]Shanghai University of Medicine&Health Sciences,No.279,Zhouzhu Road,Shanghai,China;[4]Department of Hematology,Shanghai First People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China

出　　处：《Signal Transduction and Targeted Therapy》索引2018年第3卷第1期,共10页

基　　金：This work was supported in part by grants from the National Key Research and Development Program of China(no.2017YFA0505200);the National Basic Research Program of China(973 Program)(no.2015CB910403);the National Natural Science Foundation of China(81700475,81670139,81570118,and 81570112);Natural Science Foundation of Shanghai(16ZR1427800);the Science and Technology Committee of Shanghai(15401901800);the Innovation Program of Shanghai Municipal Education Commission(13YZ028). 摘　　要：T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway.Recent studies have revealed that posttranslational modifications,such as ubiquitination,regulate NOTCH1 stability,activity,and localization.However,the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished.Here,we report that ubiquitin-specific protease 7(USP7)can stabilize NOTCH1.USP7 deubiquitinated NOTCH1 in vivo and in vitro,whereas knockdown of USP7 increased the ubiquitination of NOTCH1.USP7 interacted with NOTCH1 protein in T-ALL cells,and the MATH and UBL domains of USP7 were responsible for this interaction.Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo,accompanied by downregulation of the NOTCH1 protein level.Similarly,pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells.More importantly,we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples,and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells,indicating the clinical relevance of these findings.Overall,our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1.Therefore,USP7 may be a promising therapeutic target in the currently incurable T-ALL. 关键词：UBIQUITIN USP7 LYMPHOBLASTIC

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USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia

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