Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination.
Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination.
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DOI：
10.1084/jem.20151673
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Bao S
中科院分区：
文献类型：
--
作者：
Fang X;Zhou W;Wu Q;Huang Z;Shi Y;Yang K;Chen C;Xie Q;Mack SC;Wang X;Carcaboso AM;Sloan AE;Ouyang G;McLendon RE;Bian XW;Rich JN;Bao S
Fang等人表明，去泛素化酶USP 13通过抵消FBXL 14介导的Myc泛素化来稳定胶质母细胞瘤干细胞（GSC）中的c-Myc。c-Myc稳定化维持GSC自我更新和致瘤潜力。胶质母细胞瘤是最致命的脑肿瘤，并且含有具有强致瘤能力的胶质瘤干细胞（GSC）。GSC在肿瘤增殖中的功能由包括c-Myc在内的几种核心转录调节因子维持。c-Myc蛋白受翻译后修饰的严格调控。然而，在GSCs中c-Myc的翻译后调节机制尚未确定。在这项研究中，我们证明了去泛素化酶USP 13通过拮抗FBXL 14介导的泛素化来稳定c-Myc，以维持GSC的自我更新和致瘤潜力。USP 13优先在GSC中表达，其缺失通过促进c-Myc泛素化和降解而有效抑制GSC增殖和肿瘤生长。相反，过表达泛素E3连接酶FBXL 14诱导c-Myc降解，促进GSC分化，并抑制肿瘤生长。泛素不敏感突变体T58 A-c-Myc的异位表达挽救了FBXL 14过表达或USP 13破坏引起的效应。这些数据表明，USP 13和FBXL 14通过c-Myc的可逆泛素化在GSC的调节中发挥相反的作用。
Fang et al. show that the deubiquitinase USP13 stabilizes c-Myc in glioblastoma stem cells (GSCs) by counteracting FBXL14-mediated Myc ubiquitination. c-Myc stabilization maintains GSC self-renewal and tumorigenic potential. Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A–c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.
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影响因子：
50.3
作者：
Gargiulo, Gaetano;Cesaroni, Matteo;van Lohuizen, Maarten
通讯作者：
van Lohuizen, Maarten
影响因子：
50.3
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
通讯作者：
Phillips, Heidi S.
影响因子：
3.7
作者：
Fontaine, Jean-Fred;Mirebeau-Prunier, Delphine;Savagner, Frederique
通讯作者：
Savagner, Frederique
DOI：
10.1038/nrm2467
发表时间：
2008-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS