Amira-Talaat Moussa, Marco R Cosenza, Timothy Wohlfromm, Katharina Brobeil, Anthony Hill, Annarita Patrizi, Karin Müller-Decker, Tim Holland-Letz, Anna Jauch, Bianca Kraft, Alwin Krämer
{"title":"STIL overexpression shortens lifespan and reduces tumor formation in mice.","authors":"Amira-Talaat Moussa, Marco R Cosenza, Timothy Wohlfromm, Katharina Brobeil, Anthony Hill, Annarita Patrizi, Karin Müller-Decker, Tim Holland-Letz, Anna Jauch, Bianca Kraft, Alwin Krämer","doi":"10.1371/journal.pgen.1011460","DOIUrl":null,"url":null,"abstract":"<p><p>Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant interference with p53 function. These results suggest that supernumerary centrosomes impair proliferation in vitro as well as in vivo, resulting in reduced lifespan and delayed spontaneous as well as carcinogen-induced tumor formation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542878/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1371/journal.pgen.1011460","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant interference with p53 function. These results suggest that supernumerary centrosomes impair proliferation in vitro as well as in vivo, resulting in reduced lifespan and delayed spontaneous as well as carcinogen-induced tumor formation.
中心体是动物细胞的主要微管组织中心。超数中心体是人类肿瘤的常见特征,与核型异常和侵袭性疾病有关,但它们是癌症的原因还是结果仍存在争议。在这里,我们通过产生转基因小鼠来分析中心体扩增的后果,在转基因小鼠中,中心体结构蛋白 STIL 的过表达可以增加中心体的数量。我们发现,STIL 过表达会诱导中心体扩增和非整倍体,导致小鼠胚胎成纤维细胞衰老、凋亡和增殖受损,并导致小鼠小头畸形、围产期致死率增加和寿命缩短。重要的是,构成性、全局性 STIL 过表达的小鼠总体肿瘤形成和诱导性、皮肤特异性 STIL 过表达的动物的化学皮肤癌发生率都降低了,而同时干扰 p53 功能并不能挽救这种效应。这些结果表明,数目过多的中心体会损害体外和体内的增殖,导致寿命缩短、自发性肿瘤形成延迟以及致癌物质诱导的肿瘤形成延迟。
期刊介绍:
PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill).
Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.