USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia.
USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia.
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USP7 去泛素化并稳定 T 细胞急性淋巴细胞白血病中的 NOTCH1
DOI：
10.1038/s41392-018-0028-3
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发表时间：
2018
影响因子：
39.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Shan H;Li X;Xiao X;Dai Y;Huang J;Song J;Liu M;Yang L;Lei H;Tong Y;Zhou L;Xu H;Wu Y
T细胞急性淋巴细胞白血病(T-ALL)是一种高度侵袭性的白血病，主要由NOTCH1信号通路的异常激活引起。最近的研究表明，翻译后修饰，如泛素化，调节NOTCH1的稳定性、活性和定位。然而，影响NOTCH1蛋白稳定性的特异性去泛素酶仍未确定。在这里，我们报告了泛素特异性蛋白酶7(USP7)可以稳定NOTCH1。在体内和体外，USP7去泛素化NOTCH1，而USP7的敲除增加了NOTCH1的泛素化。在T-ALL细胞中，USP7与NOTCH1蛋白相互作用，USP7的MATH和UBL域参与了这种相互作用。在体内外，USP7的缺失显著抑制T-ALL细胞的增殖，并伴随着NOTCH1蛋白水平的下调。同样，药物抑制USP7导致T-ALL细胞凋亡。更重要的是，我们发现USP7在人类T-ALL细胞系和患者样本中显著上调，并且USP7抑制剂对原代T-ALL细胞显示出细胞毒性，表明这些发现与临床相关。总体而言，我们的结果表明USP7是一种稳定NOTCH1的新型脱泛素酶。因此，USP7可能是目前无法治愈的T-ALL的一个有前途的治疗靶点。
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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
30.8
作者：
Liu Y;Easton J;Shao Y;Maciaszek J;Wang Z;Wilkinson MR;McCastlain K;Edmonson M;Pounds SB;Shi L;Zhou X;Ma X;Sioson E;Li Y;Rusch M;Gupta P;Pei D;Cheng C;Smith MA;Auvil JG;Gerhard DS;Relling MV;Winick NJ;Carroll AJ;Heerema NA;Raetz E;Devidas M;Willman CL;Harvey RC;Carroll WL;Dunsmore KP;Winter SS;Wood BL;Sorrentino BP;Downing JR;Loh ML;Hunger SP;Zhang J;Mullighan CG
通讯作者：
Mullighan CG
影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1615/critreveukaryotgeneexpr.2016016587
发表时间：
2016-01-01
影响因子：
1.6
作者：
Gao, Lingbao;Yuan, Keyu;Lin, Mei
通讯作者：
Lin, Mei
影响因子：
4.8
作者：
Jehn, BM;Dittert, I;Bielke, W
通讯作者：
Bielke, W