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

点击翻译按钮获取中文摘要

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.