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Bub1 过表达通过激活 Aurora B 激酶诱导非整倍体和肿瘤形成。

Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.

机构信息

Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.

出版信息

J Cell Biol. 2011 Jun 13;193(6):1049-64. doi: 10.1083/jcb.201012035. Epub 2011 Jun 6.

DOI:10.1083/jcb.201012035
PMID:21646403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3115799/
Abstract

High expression of the protein kinase Bub1 has been observed in a variety of human tumors and often correlates with poor clinical prognosis, but its molecular and cellular consequences and role in tumorigenesis are unknown. Here, we demonstrate that overexpression of Bub1 in mice leads to near-diploid aneuploidies and tumor formation. We found that chromosome misalignment and lagging are the primary mitotic errors responsible for the observed aneuploidization. High Bub1 levels resulted in aberrant Bub1 kinase activity and hyperactivation of Aurora B kinase. When Aurora B activity is suppressed, pharmacologically or via BubR1 overexpression, chromosome segregation errors caused by Bub1 overexpression are largely corrected. Importantly, Bub1 transgenic mice overexpressing Bub1 developed various kinds of spontaneous tumors and showed accelerated Myc-induced lymphomagenesis. Our results establish that Bub1 has oncogenic properties and suggest that Aurora B is a critical target through which overexpressed Bub1 drives aneuploidization and tumorigenesis.

摘要

蛋白激酶 Bub1 的高表达已在多种人类肿瘤中观察到，且常与不良的临床预后相关，但它在肿瘤发生中的分子和细胞后果及作用尚不清楚。在这里，我们证明了在小鼠中过表达 Bub1 会导致近二倍体非整倍体和肿瘤形成。我们发现染色体错位和滞后是导致观察到的非整倍体的主要有丝分裂错误。高 Bub1 水平导致异常的 Bub1 激酶活性和 Aurora B 激酶的过度激活。当抑制 Aurora B 的活性时，通过药理学或过表达 BubR1，由 Bub1 过表达引起的染色体分离错误得到了很大程度的纠正。重要的是，过表达 Bub1 的 Bub1 转基因小鼠发展出各种自发肿瘤，并表现出加速的 Myc 诱导的淋巴瘤发生。我们的结果确立了 Bub1 具有致癌特性，并表明 Aurora B 是一个关键靶点，通过该靶点，过表达的 Bub1 驱动非整倍体形成和肿瘤发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/33a9c571bb0b/JCB_201012035_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/aeff1dac9f5a/JCB_201012035_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/4bfeefbd20be/JCB_201012035_GS_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/cf0ad154198c/JCB_201012035_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/471f8ae0926a/JCB_201012035R_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/dc96612e8b62/JCB_201012035R_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/a7186fa43091/JCB_201012035R_RGB_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/33a9c571bb0b/JCB_201012035_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/aeff1dac9f5a/JCB_201012035_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/4bfeefbd20be/JCB_201012035_GS_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/cf0ad154198c/JCB_201012035_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/471f8ae0926a/JCB_201012035R_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/dc96612e8b62/JCB_201012035R_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/a7186fa43091/JCB_201012035R_RGB_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/796f/3115799/33a9c571bb0b/JCB_201012035_RGB_Fig7.jpg

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