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

肝细胞癌的一个重要特征是高度的染色体不稳定性。人们对遗传不稳定的形成机制只有部分了解。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，从而导致子细胞之间染色体的平等分离。众所周知，肝细胞癌包含带有额外中心体的细胞，中心体的数量与非整倍体的程度有关。一个中心和目前尚未解决的问题是中心体异常是肿瘤形成的原因还是结果。在这个项目中，我们将研究SCFFbxw5泛素连接酶在这一过程中的作用。我们最近发现，这种E3-泛素连接酶对于中心体蛋白HSAs-6的降解至关重要，而HSAs-6又是中心体复制的起始者之一。在描述了这一分子机制之后，我们现在将在可诱导的小鼠模型中研究Fbxw5的功能，并确定在细胞转化过程中与Fbxw5丢失协同作用的遗传事件。

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.