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New role for the APC gene in chromosome segregation and stability
  
By Bijal P. Trivedi

Two teams of researchers have identified a new role for the APC (Adenomatous Polyposis Coli) tumor suppressor gene. Recent experiments show APC ensures that each daughter cell receives the correct number of chromosomes when the parent cell divides. Mouse cells with a mutant version of APC contained either too many or too few chromosomes, a situation called chromosomal instability. Irregular numbers of chromosomes is a hallmark of many cancers. Now these researchers believe that loss of APC may be a cause.

The team led by Riccardo Fodde, of Leiden University Medical Center, in The Netherlands, engineered mouse cells containing one of two shortened versions of the APC gene. Cells carrying either of the APC mutants had an abnormal number of chromosomes. In addition, many of the chromosomes had structural deformities; some were fusions of up to three different chromosomes. These results are published in the current issue of Nature Cell Biology.



LEFT: a wild-type mouse cell with the expected spread of 40 (20 pairs) chromosomes. Each chromosome is a single color.
RIGHT: When the APC gene is specifically inactivated in a mouse cell, the result is chromosomal instability. This mouse cell shows a collection of more than 40 chromosomes. Many of the chromosomes shown are actually fusions of several chromosomes, hence the rainbow-like appearance.


Both Fodde's team and the Anglo-American team, led by Kenneth Kaplan, of the University of California, Davis, found that the APC protein is an essential part of the machinery that enables chromosomes to divide evenly among two cells at the time of cell division.

When a cell gets ready to divide each chromosome becomes a compact bundle, shaped like a bowtie. The narrowest part of the bowtie resembles a cluster of proteins called a kinetochore, which includes APC. When the cell is ready to split, tiny fibers projecting from opposite poles of the cell grab each chromosome at the kinetochore and yank it to one of the poles. In a normal cell, an equal number of chromosomes end up at each pole and then the cell splits. In cells carrying a mutated APC gene the fibers are unable to grab the kinetochore and cannot efficiently move chromosomes to the poles.

Mutations in the APC gene are known to cause hereditary forms of colon cancer. The gene is frequently mutated during early stages of non-hereditary colon cancers.

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Kaplan, K.B. et al. A role for the adenomatous polyposis coli protein in chromosome segregation. Nat Cell Biol 3, 429-432 (April 2001).
 
Fodde, R. et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3, 433-438 (April 2001).
 

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