TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation.
TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation.
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TRIB3通过抑制UBE3B介导的MYC降解促进MYC相关淋巴瘤的发展。
DOI：
10.1038/s41467-020-20107-1
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发表时间：
2020-12-09
影响因子：
16.6
通讯作者：
Hu ZW
中科院分区：
文献类型：
--
作者：
Li K;Wang F;Yang ZN;Zhang TT;Yuan YF;Zhao CX;Yeerjiang Z;Cui B;Hua F;Lv XX;Zhang XW;Yu JJ;Liu SS;Yu JM;Shang S;Xiao Y;Hu ZW
转录因子MYC在几乎所有人类癌症中，特别是在侵袭性淋巴瘤中，通过染色体易位、扩增和转录过度活化而被失调。在这里，我们报告说，高表达的tribbles同源物3（TRIB 3）与淋巴瘤标本中MYC表达升高呈正相关; TRIB 3缺失通过减少MYC表达减弱MYC驱动的淋巴瘤的发生和进展。从机制上讲，TRIB 3与MYC相互作用以抑制E3泛素连接酶UBE 3B介导的MYC泛素化和降解，这增强了MYC转录活性，导致淋巴瘤细胞的高度增殖和自我更新。使用肽干扰TRIB 3-MYC相互作用与多柔比星一起降低了MycEμ小鼠和患者来源的异种移植物中的肿瘤负荷。在人类淋巴瘤中进一步证实了UBE 3B、TRIB 3和MYC的病理生理学相关性。我们的研究强调了控制MYC表达的关键机制和治疗TRIB 3-MYC高表达淋巴瘤的潜在治疗选择。c-MYC通常在包括淋巴瘤在内的人类癌症中失调。在这里，作者表明，假激酶家族的一个成员，tribbles同系物3（TRIB 3），与c-MYC相互作用，抑制c-MYC泛素化和降解，导致淋巴瘤细胞增殖和自我更新增加。
The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in MycEμ mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression. c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.
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影响因子：
20.1
作者：
Avery J;Etzion S;DeBosch BJ;Jin X;Lupu TS;Beitinjaneh B;Grand J;Kovacs A;Sambandam N;Muslin AJ
通讯作者：
Muslin AJ
影响因子：
3.7
作者：
Chakraborty, Abhishek A.;Tansey, William P.
通讯作者：
Tansey, William P.
影响因子：
9.8
作者：
Basel-Vanagaite, Lina;Dallapiccola, Bruno;Borck, Guntram
通讯作者：
Borck, Guntram
影响因子：
45.3
作者：
Cheson, Bruce D.;Fisher, Richard I.;Lister, T. Andrew
通讯作者：
Lister, T. Andrew
DOI：
10.1038/nrc.2017.36
发表时间：
2017-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Dang CV;Reddy EP;Shokat KM;Soucek L
通讯作者：
Soucek L