The role of centrosome duplication errors in the formation of hepatocellular carcinomas

中心体重复错误在肝细胞癌形成中的作用

• 批准号: 231402484
• 负责人: Professor Dr. Nisar Peter Malek
• 金额: --
• 依托单位: Swiss Institute for Experimental Cancer (ISREC)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/231402484?language=en
• 关键词: role; centrosome; duplication; errors; formation

A central property of hepatocellular carcinomas (HCC) is the high degree of chromosomal instability. The mechanisms involved in the formation of genetic instability are only partly understood. Centrosomes play a central role in maintaining genetic stability as they are responsible for the formation of the mitotic spindle and hence the equal separation of chromosomes between the daughter cells. HCC are known to contain cells with additional centrosomes and the number of centrosomes correlates with the degree of aneuploidy. A central and currently unsolved question is whether centrosome abnormalities are the cause or the consequence of tumor formation. Within this project we will study the role of the SCFFbxw5 ubiquitin ligase within this process. We recently showed that this E3-ubiquitin ligase is of central importance for the degradation of the centrosomal protein hSAS-6 which in turn is one of the initiators of centrosome duplication. After describing this molecular mechanism we will now study the function of Fbxw5 in an inducible mouse model and identify collaborating genetic events that synergize with the loss of Fbxw5 in the transformation of cells.

肝细胞癌（HCC）的一个核心特性是高度的染色体不稳定性。遗传不稳定性形成的机制只被部分理解。中心体在维持遗传稳定性方面起着核心作用，因为它们负责有丝分裂纺锤体的形成，因此子细胞之间的染色体相等分离。已知HCC含有具有额外中心体的细胞，并且中心体的数量与非整倍性的程度相关。中心体异常是肿瘤形成的原因还是结果，是一个中心且目前尚未解决的问题。在这个项目中，我们将研究SCFFbxw 5泛素连接酶在这个过程中的作用。我们最近发现，E3-泛素连接酶是中心体蛋白HSAS-6的降解，这反过来又是中心体复制的启动子之一的核心重要性。在描述了这种分子机制之后，我们现在将在诱导型小鼠模型中研究Fbxw 5的功能，并鉴定在细胞转化中与Fbxw 5损失协同作用的协作遗传事件。