Disorderly protein brings order to cell division

The secret to the ability of a molecule critical for cell division to throw off the protein yoke that restrains its activity is the yoke itself - a disorderly molecule that seems to have a mind of its own, say investigators at St. Jude, the Innsbruck Medical University (Austria) and the Max Planck Institute (Martinsried, Germany).

A report on their work appears in the January 25 issue of the journal Cell.

The researchers showed that the disorderly protein yoke, called p27, participates in its own destruction by swinging the end of its long arm up into a key side pocket of the cell division molecule, called CDK2. After the end of p27 slips into the pocket, CDK2 marks p27 for destruction by tagging it with a molecule called phosphate. The tag signals the cell's protein destruction machinery to dispose of p27, freeing CDK2 to trigger cell division. However, in order for the long arm of p27 to swing up into the pocket, an enzyme called a kinase must first remove the upper part of p27 that is lodged in the pocket by tagging it with phosphate. Only then is there room for the far end of p27 to insert itself.

The findings explain how CDK2 normally shrugs off p27 and how some abnormal enzymes cause this to occur prematurely, putting cell division into overdrive—a state that produces cancer, noted co-senior author Richard Kriwacki, PhD, Structural Biology.

The results also show why the anti-cancer drug Gleevec is effective in treating some forms of leukemia in certain individuals, said Yuefeng Wang, PhD a postdoctoral student in Kriwacki's laboratory who did much of the work on this project and is a co-first author.

Gleevec blocks the abnormal kinase BCR-ABL and prevents it from tagging the upper part of p27 lodged in the pocket of CDK2, Wang said. This, in turn, prevents the lower part of p27 from swinging up into the pocket.

"Blocking the CDK2 pocket after an abnormal tyrosine kinase dislodges the p27 elbow might be an effective future strategy for preventing cancerous cell division in these cells," Kriwacki said.

Brett Waddell, Hartwell Center, also contributed to this paper.


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