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Consequences of supernumerary centrioles in STIL-transgenic mice

STIL 转基因小鼠中多余中心粒的后果

基本信息

批准号：
286748964
负责人：
Professor Dr. Alwin Krämer
金额：
--
依托单位：
Klinik für Hämatologie, Onkologie und Rheumatologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/286748964?language=en
关键词：
Consequences supernumerary centrioles STIL transgenic

项目摘要

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.

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，它们指导双极纺锤体的形成，这是精确染色体分离所必需的过程。额外中心体是癌细胞的标志，并且被假定可能通过促进染色体不稳定性（CIN）而促成肿瘤发生。在哺乳动物细胞中，中心粒复制仅由少数蛋白质控制，其中之一是STIL，其过表达导致中心粒过量产生，随后在体外产生CIN。额外中心体是否引起CIN和随后的体内肿瘤形成仍然是难以捉摸的。为了研究体内中心粒过度产生的后果，我们已经产生了一个小鼠模型，其中中心粒复制蛋白STIL以有条件的方式过表达。这些小鼠将允许检查额外中心体和CIN对不同器官系统和遗传背景中肿瘤形成和/或进展的贡献。此外，额外的中心粒导致CIN在体内的机制可以检查。最后，如果STIL过表达小鼠发生恶性肿瘤，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功效。