Related Experiment Video
Updated: Jun 9, 2025
Forward Genetic Approach to Uncover Stress Resistance Genes in Mice — A High-throughput Screen in ES Cells
Published on: November 11, 2015
STIL overexpression shortens lifespan and reduces tumor formation in mice
Amira-Talaat Moussa1,2, Marco R Cosenza1,3, Timothy Wohlfromm1
1Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
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.
Insights
Supernumerary centrosomes, caused by STIL overexpression, lead to cell death and impaired growth in mice. This surprising finding reveals that extra centrosomes actually reduce tumor formation and lifespan.
Area of Science:
- Cell Biology
- Cancer Biology
- Genetics
Background:
- Centrosomes are key microtubule organizing centers in animal cells.
- Supernumerary centrosomes are frequently observed in human tumors, but their causal role in cancer is debated.
Purpose of the Study:
- To investigate the consequences of centrosome amplification in vivo.
- To determine if increased centrosome numbers contribute to or protect against cancer.
Main Methods:
- Generated transgenic mice overexpressing the structural centrosome protein STIL to induce centrosome amplification.
- Analyzed effects on mouse embryonic fibroblasts (MEFs) and overall tumor formation.
- Assessed chemical skin carcinogenesis in inducible transgenic mice.
- Investigated the role of p53 in mediating these effects.
Main Results:
- STIL overexpression caused centrosome amplification, aneuploidy, senescence, apoptosis, and impaired proliferation in MEFs.
- Mice with STIL overexpression exhibited microcephaly, increased perinatal lethality, and shortened lifespan.
- Both spontaneous and carcinogen-induced tumor formation were reduced in STIL-overexpressing mice.
- Interference with p53 function did not rescue the tumor-suppressive effects.
Conclusions:
- Supernumerary centrosomes act as a barrier to proliferation in vitro and in vivo.
- Centrosome amplification can delay or reduce tumor formation, suggesting a non-canonical tumor-suppressive role.
- These findings challenge the long-held view of supernumerary centrosomes solely as drivers of cancer progression.
More Related Videos
08:34Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
11:47Time-lapse Imaging of Primary Preneoplastic Mammary Epithelial Cells Derived from Genetically Engineered Mouse Models of Breast Cancer
Published on: February 8, 2013
Related Concept Videos
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:15Replicative Cell Senescence
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:16In-vitro Mutagenesis