CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia.
CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia.
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CUEDC2 是 SOCS1 蛋白的新型相互作用伙伴，在急性髓性白血病的白血病发生中发挥重要作用。
DOI：
10.1038/s41419-018-0812-6
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发表时间：
2018-07-10
影响因子：
9
通讯作者：
Xu KL
中科院分区：
文献类型：
--
作者：
Wu QY;Zhu YY;Liu Y;Wei F;Tong YX;Cao J;Zhou P;Niu MS;Li ZY;Zeng LY;Li F;Xu KL
细胞因子信号传导抑制因子1 （SOCS1）的下调是急性髓性白血病（AML）中JAK1-STAT3通路激活的重要原因之一。含CUE结构域2 （CUEDC2）是SOCS1的一个新的相互作用伙伴，在原发性AML细胞和未发生SOCS1启动子甲基化的AML细胞系中证实了CUEDC2和SOCS1的表达呈正相关。我们旨在探讨CUEDC2在AML白血病发生过程中调控泛素介导的SOCS1降解中的作用。体外实验表明，CUEDC2过表达可提高SOCS1蛋白水平，抑制JAK1-STAT3通路激活。抑制该通路通过引起G1阻滞抑制AML细胞增殖，增强AML细胞对阿糖胞苷和伊达柔比星的敏感性。相似的是，下调CUEDC2产生相反的结果。与CUEDC2高表达的小鼠和AML患者相比，敲除或低表达CUEDC2的小鼠或AML患者的总生存率和无事件生存率较低。机制研究表明，CUEDC2过表达可减弱SOCS1泛素化，通过增强SOCS1、长链蛋白C和culin -2 （CUL2）的相互作用促进其稳定，从而抑制JAK1-STAT3通路和AML的白血病发生。因此，我们的新发现表明，CUEDC2与SOCS1相互作用，抑制SOCS1的泛素介导的降解、JAK1-STAT3通路激活和AML的白血病发生。
Downregulation of suppressor of cytokine signalling-1 (SOCS1) is one of the vital reasons for JAK1-STAT3 pathway activation in acute myeloid leukaemia (AML). CUE domain-containing 2 (CUEDC2) was a novel interacting partner of SOCS1 and a positive correlation between the expression of CUEDC2 and SOCS1 was confirmed in primary AML cells and AML cell lines without SOCS1 promoter methylation. We aimed to explore roles of CUEDC2 in regulating ubiquitin-mediated degradation of SOCS1 in the leukaemogenesis of AML. According to in vitro experiments, CUEDC2 overexpression increased the level of SOCS1 protein, suppressed JAK1-STAT3 pathway activation. The suppression of this pathway inhibited AML cells’ proliferation by causing G1 arrest and enhanced AML cells’ sensitivity to cytarabine and idarubicin. Similarity, downregulation of CUEDC2 produced opposite results. Knockout or low expression of CUEDC2 in mouse or AML patients displayed lower overall survival and event-free survival rates, compared with these mouse and AML patients had high-CUEDC2 expression. Mechanistic studies revealed that CUEDC2 overexpression attenuated SOCS1 ubiquitination, facilitated its stabilisation by enhancing SOCS1, Elongin C and Cullin-2 (CUL2) interactions, thus inhibited JAK1-STAT3 pathway and leukaemogenesis of AML. Therefore, our novel findings indicated that CUEDC2 interacted with SOCS1 to suppress SOCS1’s ubiquitin-mediated degradation, JAK1-STAT3 pathway activation and leukaemogenesis of AML.
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CUEDC2通过抑制STAT3和NF-κB信号通路的激活来抑制胶质瘤致瘤性
影响因子：
5.2
作者：
Li F;Tang C;Jin D;Guan L;Wu Y;Liu X;Wu X;Wu QY;Gao D
通讯作者：
Gao D
影响因子：
82.9
作者：
Pan, Xin;Zhou, Tao;Zhang, Xue-Min
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Zhang, Xue-Min
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影响因子：
16.8
作者：
Palmer DC;Restifo NP
通讯作者：
Restifo NP
影响因子：
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作者：
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通讯作者：
Conaway, JW
影响因子：
30.5
作者：
Li, Hui-Yan;Liu, Hui;Zhang, Xue-Min
通讯作者：
Zhang, Xue-Min