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Tumor suppressor p53 prevents cancer progression in cells with missegregated chromosomes
Date:2/1/2010

Cells missegregate a chromosome approximately once every hundred divisions. But don't be too alarmed: new research in the Journal of Cell Biology shows that the tumor suppressor p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer. The study appears online February 1 (www.jcb.org).

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
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Contact: Rita Sullivan
news@rupress.org
212-327-8603
Rockefeller University Press
Source:Eurekalert  

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