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泛素连接酶 RNF20/40 通过稳定驱动蛋白 Eg5 促进纺锤体组装并促进乳腺癌发生。

Ubiquitin ligase RNF20/40 facilitates spindle assembly and promotes breast carcinogenesis through stabilizing motor protein Eg5.

机构信息

Department of Biochemistry and Molecular Biology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.

Tianjin Key Laboratory of Lung Cancer Metastasis and Tumour Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.

出版信息

Nat Commun. 2016 Aug 25;7:12648. doi: 10.1038/ncomms12648.

DOI:10.1038/ncomms12648
PMID:27557628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5007379/
Abstract

Whether transcriptional regulators are functionally involved in mitosis is a fundamental question in cell biology. Here we report that the RNF20/40 complex, a major ubiquitin ligase catalysing histone H2B monoubiquitination, interacts with the motor protein Eg5 during mitosis and participates in spindle assembly. We show that the RNF20/40 complex monoubiquitinates and stabilizes Eg5. Loss of RNF20/40 results in spindle assembly defects, cell cycle arrest and apoptosis. Consistently, depletion of either RNF20/40 or Eg5 suppresses breast cancer in vivo. Significantly, RNF20/40 and Eg5 are concurrently upregulated in human breast carcinomas and high Eg5 expression is associated with poorer overall survival of patients with luminal A, or B, breast cancer. Our study uncovers an important spindle assembly role of the RNF20/40 complex, and implicates the RNF20/40-Eg5 axis in breast carcinogenesis, supporting the pursuit of these proteins as potential targets for breast cancer therapeutic interventions.

摘要

转录调控因子是否参与有丝分裂是细胞生物学中的一个基本问题。在这里，我们报告说，RNF20/40 复合物，一种主要的泛素连接酶，催化组蛋白 H2B 的单泛素化，在有丝分裂过程中与马达蛋白 Eg5 相互作用，并参与纺锤体的组装。我们表明，RNF20/40 复合物单泛素化并稳定 Eg5。RNF20/40 的缺失导致纺锤体组装缺陷、细胞周期停滞和细胞凋亡。一致地，RNF20/40 或 Eg5 的缺失都抑制了体内的乳腺癌。重要的是，RNF20/40 和 Eg5 在人类乳腺癌中同时被上调，并且高表达 Eg5 与腔 A 或 B 型乳腺癌患者的总生存期较差相关。我们的研究揭示了 RNF20/40 复合物在纺锤体组装中的重要作用，并暗示了 RNF20/40-Eg5 轴在乳腺癌发生中的作用，支持将这些蛋白作为乳腺癌治疗干预的潜在靶点进行研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/ca5209d32514/ncomms12648-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/fcdb61cf9543/ncomms12648-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/033aacb9b730/ncomms12648-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/df19b8335992/ncomms12648-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/d522c6a2bded/ncomms12648-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/ca5209d32514/ncomms12648-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/fcdb61cf9543/ncomms12648-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/3cfb3113aa2b/ncomms12648-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/de50db9bdb80/ncomms12648-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/033aacb9b730/ncomms12648-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/df19b8335992/ncomms12648-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/d522c6a2bded/ncomms12648-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75e3/5007379/ca5209d32514/ncomms12648-f7.jpg

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