miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.
miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.
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DOI：
10.1038/s41420-023-01537-4
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发表时间：
2023-07-15
影响因子：
7
通讯作者：
Chen, Yun
中科院分区：
文献类型：
--
作者：
Pei, Han Zhong;Peng, Zhiyong;Zhuang, Xiaomei;Wang, Xiaobo;Lu, Bo;Guo, Yao;Zhao, Yuming;Zhang, Dengyang;Xiao, Yunjun;Gao, Tianshun;Yu, Liuting;He, Chunxiao;Wu, Shunjie;Baek, Suk-Hwan;Zhao, Zhizhuang Joe;Xu, Xiaojun;Chen, Yun
急性髓性白血病（AML）是一种以骨髓原始细胞分化受损和增殖失控为特征的血液恶性肿瘤。肿瘤抑制因子p53通常通过泛素化介导的降解在AML细胞中下调。虽然E3连接酶MDM 2在p53泛素化中的作用是公认的，但对去泛素化酶（DUB）的参与知之甚少。在此，我们发现在几种DUB中，YOD 1的表达在来自AML患者的血细胞中显著降低。我们鉴定了YOD 1通过经由p53的N-末端和YOD 1的OTU结构域的相互作用去泛素化和稳定p53。此外，报告基因分析证实，AML细胞中miR-221/222通过与YOD 1的3′非翻译区结合，抑制了YOD 1的表达水平。用miR-221/222模拟物和抑制剂处理细胞对YOD 1表达产生了预期的影响，这与AML细胞中miR-221/222和YOD 1表达水平之间观察到的负相关性一致。最后，YOD 1的过表达稳定了p53，上调了促凋亡p53下游基因，并显著增加了AML细胞对FLT 3抑制剂的敏感性。总的来说，我们的研究确定了AML中连接miR-221/222，YOD 1和p53的途径。靶向miR-221/222并刺激YOD 1活性可能会改善AML患者中FLT 3抑制剂的治疗效果。
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3′ untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.
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影响因子：
8
作者：
Aziz, M. H.;Shen, H.;Maki, C. G.
通讯作者：
Maki, C. G.
影响因子：
5.1
作者：
Ke, Jia-ying;Dai, Cong-jie;Wu, Chun-lin
通讯作者：
Wu, Chun-lin
DOI：
10.1007/978-3-642-01222-8_5
发表时间：
2010-01-01
期刊：
SMALL MOLECULES IN ONCOLOGY
影响因子：
--
作者：
Hasskarl, Jens
通讯作者：
Hasskarl, Jens
影响因子：
20.3
作者：
Chen, Yun;Chen, Liguang;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
16.6
作者：
Fernandez-Majada, Vanesa;Welz, Patrick-Simon;Ermolaeva, Maria A.;Schell, Michael;Adam, Alexander;Dietlein, Felix;Komander, David;Buettner, Reinhard;Thomas, Roman K.;Schumacher, Bjoern;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis