| Autor: |
Moussa, Amira-Talaat, Cosenza, Marco R., Wohlfromm, Timothy, Brobeil, Katharina, Hill, Anthony, Patrizi, Annarita, Müller-Decker, Karin, Holland-Letz, Tim, Jauch, Anna, Kraft, Bianca, Krämer, Alwin |
| Předmět: |
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| Zdroj: |
PLoS Genetics; 10/28/2024, Vol. 20 Issue 10, p1-28, 28p |
| Abstrakt: |
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. Author summary: Already at the beginning of the last century, Theodor Boveri suggested that supernumerary centrosomes might be a cause of cancer via the generation of abnormal mitotic spindles and subsequent chromosome missegregation. In the meantime, centrosome amplification has been observed in most tumor types and is viewed as a "hallmark" of cancer cells. However, studies on tumor formation in mice by overexpression of PLK4, the principal kinase regulating centrosome duplication, led to ambiguous results, as some but not all models resulted in increased tumorigenesis. In this study, we generated transgenic mice, which overexpress the structural centrosome protein STIL. Similar to PLK4, overexpression of STIL caused centrosome amplification and aneuploidy in mouse cells. Our analyses revealed that powerful mechanisms lead to the elimination of cells with extra centrosomes and/or aneuploidy by impaired proliferation, senescence and apoptosis, thereby delaying both spontaneous tumor formation and chemical skin carcinogenesis, and explaining the reduced life span of STIL-transgenic mice. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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