Consequences of supernumerary centrioles in STIL-transgenic mice

中心体由一对中心粒组成，是动物细胞的主要微管组织中心。中心粒复制受到精确控制，因此有丝分裂细胞正好有两个中心体，这两个中心体指导着两极纺锤体的形成，这一过程对于准确的染色体分离至关重要。额外的中心体是癌细胞的一个标志，并被认为有助于肿瘤的发生，可能是通过促进染色体不稳定(CIN)。在哺乳动物细胞中，中心粒的复制只受几种蛋白质的控制，其中一种是STIL，它的过度表达导致中心粒在体外产生过量的CIN。是否多余的中心体在体内引起CIN和随后的肿瘤形成仍然难以捉摸。为了研究体内中心粒过度生产的后果，我们建立了一个小鼠模型，其中中心粒复制蛋白STIL以有条件的方式过度表达。这些小鼠将能够检测额外的中心体和CIN在不同器官系统和遗传背景下对肿瘤形成和/或进展的贡献。此外，额外的中心粒在体内导致CIN的机制也可以被研究。最后，如果STIL过表达的小鼠发生恶性肿瘤，那么这些动物非常适合作为临床前模型来研究新型CIN和中心体靶向抗癌药物的疗效。

Centrosomes consist of a pair of centrioles and act as the major microtubule-organizing centers of animal cells. Centriole duplication is precisely controlled so that mitotic cells have exactly two centrosomes which direct the formation of bipolar spindles, a process essential for accurate chromosome segregation. Supernumerary centrosomes are a hallmark of cancer cells and have been postulated to contribute to tumorigenesis, perhaps by promoting chromosomal instability (CIN). In mammalian cells, centriole replication is controlled by only a few proteins, one of them being STIL, whose overexpression leads to centriole overproduction with subsequent CIN in vitro. Whether or not supernumerary centrosomes cause CIN and subsequent tumor formation in vivo is still elusive. In order to investigate the consequences of centriole overproduction in vivo, we have generated a mouse model, where the centriole replication protein STIL is overexpressed in a conditional manner. These mice will allow to examine the contribution of both supernumerary centrosomes and CIN to tumor formation and/or progression in different organ systems and genetic backgrounds. Also, the mechanisms by which extra centrioles lead to CIN in vivo can be examined. Finally, if STIL-overexpressing mice develop malignancies, then these animal are well suited as a preclinical model to study the efficacy of novel CIN- and centrosome-targeting anti-cancer drugs.