Tumor cells tend to missegregate chromosomes at a particularly high frequency (a condition known as chromosomal instability, or CIN), which is probably why they are often aneuploid (i.e., they carry an abnormal number of chromosomes).
In 2008, Sarah Thompson and Duane Compton, from Dartmouth Medical School, revealed that most CIN in tumor cells was caused by incorrect attachments between mitotic spindle microtubules and kinetochores, and that inducing misattachments in normal cells was sufficient to generate high rates of chromosome missegregation. There was a small but significant wrinkle to this story, however: normal, diploid cells stopped proliferating as soon as they gained or lost a chromosome, so they never converted into a cancer-like aneuploid cell line.
To investigate why normal cells stop proliferating when they missegregate their DNA, Thompson and Compton engineered a human cell line to carry a unique fluorescent mark on one of its chromosomes. This allowed them to identify and follow by live microscopy the cells that missegregated a chromosome.
The researchers induced missegregation and then looked for cells that had gained or lost a fluorescent mark within their genome. These cells failed to proliferate, and showed elevated levels of p53 and one of its transcriptional targets, the cell cycle inhibitor p21. Cells lacking p53 became aneuploid after induced missegregation, indicating that the p53 pathway normally serves to limit the propagation of cells with odd numbers of chromosomes.
How is p53 activated by chromosome missegregation? Thompson and Compton think that a change in chromosome number leads to an imbalance in gene expression, resulting in a stress response and cell cycle arrest that is vital to avoid cancer. "By combining loss of p53 with increased missegregation rates, we can convert a diploid cell into something …. that looks like a tumor cell," says Compton. Furthermore, these aneuploid cells develop an inherent genomic instability reminiscent of genuine cancer cells, perhaps because imbalanced gene expression also causes disruptions to mitosis.
A recent study demonstrated that chromosome missegregation initiates tumorigenesis by causing cells to lose tumor suppressors like p53. "It's like a self-fulfilling prophecy," argues Compton. "If you missegregate a chromosome encoding p53, you make the cells deficient in p53, so they're able to propagate and missegregate more chromosomes."
There are circumstances in which nontumor cells tolerate aneuploidy just fine, but, in most cases, healthy cells keep a tight check on chromosome number. "I think it affects a lot of different pathways," says Compton. "The next question to ask is which pathways are sensitive to aneuploidy, and how do tumor cells overcome those problems?"
About The Journal of Cell Biology
Founded in 1955, The Journal of Cell Biology (JCB) is published by The Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editors. JCB content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit www.jcb.org.
Thompson, S.L., and D.A. Compton. 2010. J. Cell Biol. doi:10.1083/jcb. 200905057.
Rita Sullivan | EurekAlert!
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering
06.12.2016 | Power and Electrical Engineering