Hec1过表达会过度激活有丝分裂检查点并在体内诱导肿瘤形成。
Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo.
作者信息
Diaz-Rodríguez Elena, Sotillo Rocio, Schvartzman Juan-Manuel, Benezra Robert
机构信息
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16719-24. doi: 10.1073/pnas.0803504105. Epub 2008 Oct 21.
Abstract
Hec1 (Highly Expressed in Cancer 1) is one of four proteins of the outer kinetochore Ndc80 complex involved in the dynamic interface between centromeres and spindle microtubules. Its overexpression is seen in a variety of human tumors and correlates with tumor grade and prognosis. We show here that the overexpression of Hec1 in an inducible mouse model results in mitotic checkpoint hyperactivation. As previously observed with overexpression of the Mad2 gene, hyperactivation of the mitotic checkpoint leads to aneuploidy in vitro and is sufficient to generate tumors in vivo that harbor significant levels of aneuploidy. These results underscore the role of chromosomal instability as a result of mitotic checkpoint hyperactivation in the initiation of tumorigenesis.
摘要
Hec1（癌症高表达蛋白1）是外着丝粒Ndc80复合物的四种蛋白质之一，参与着丝粒与纺锤体微管之间的动态界面。在多种人类肿瘤中都可见其过表达，且与肿瘤分级和预后相关。我们在此表明，在可诱导的小鼠模型中Hec1的过表达会导致有丝分裂检查点过度激活。正如之前在Mad2基因过表达时所观察到的那样，有丝分裂检查点的过度激活在体外会导致非整倍体，并且足以在体内产生具有显著非整倍体水平的肿瘤。这些结果强调了有丝分裂检查点过度激活导致的染色体不稳定性在肿瘤发生起始过程中的作用。
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本文引用的文献
1
The Ndc80 complex: hub of kinetochore activity.Ndc80复合体：动粒活动的中心
FEBS Lett. 2007 Jun 19;581(15):2862-9. doi: 10.1016/j.febslet.2007.05.012. Epub 2007 May 11.
2
Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors.后期促进复合物/细胞周期体的致癌调节因子和底物在恶性肿瘤中经常过度表达。
Am J Pathol. 2007 May;170(5):1793-805. doi: 10.2353/ajpath.2007.060767.
3
The spindle-assembly checkpoint in space and time.时空维度下的纺锤体组装检查点
Nat Rev Mol Cell Biol. 2007 May;8(5):379-93. doi: 10.1038/nrm2163. Epub 2007 Apr 11.
4
A mutation in separase causes genome instability and increased susceptibility to epithelial cancer.Separase基因的突变会导致基因组不稳定，并增加患上皮癌的易感性。
Genes Dev. 2007 Jan 1;21(1):55-9. doi: 10.1101/gad.1470407.
5
The Ndc80/HEC1 complex is a contact point for kinetochore-microtubule attachment.Ndc80/HEC1复合体是动粒与微管附着的接触点。
Nat Struct Mol Biol. 2007 Jan;14(1):54-9. doi: 10.1038/nsmb1186. Epub 2006 Dec 31.
6
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Cancer Cell. 2007 Jan;11(1):25-36. doi: 10.1016/j.ccr.2006.12.003. Epub 2006 Dec 28.
7
Mad2 overexpression promotes aneuploidy and tumorigenesis in mice.Mad2过表达促进小鼠非整倍体形成和肿瘤发生。
Cancer Cell. 2007 Jan;11(1):9-23. doi: 10.1016/j.ccr.2006.10.019. Epub 2006 Dec 28.
8
The conserved KMN network constitutes the core microtubule-binding site of the kinetochore.保守的KMN网络构成了动粒的核心微管结合位点。
Cell. 2006 Dec 1;127(5):983-97. doi: 10.1016/j.cell.2006.09.039.
9
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Cell. 2006 Dec 1;127(5):969-82. doi: 10.1016/j.cell.2006.09.047.
10
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Cancer Res. 2006 Nov 1;66(21):10339-48. doi: 10.1158/0008-5472.CAN-06-2137.
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