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 Children's Research Hospital, Innsbruck Medical University (Austria) and Max Planck Institute (Martinsried, Germany).

A report on the 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 are important because it explains 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, said Richard Kriwacki, Ph.D., associate member in the Department of Structural Biology at St. Jude and co-senior author of the paper.

"The results also show why the anti-cancer drug Gleevec(R) is effective in treating some forms of leukemia in certain individuals," said Yuefeng Wang, Ph.D., a postdoctoral student in Kriwacki's laboratory who did much of the work on this project. "Gleevec blocks the abnormal kinase BCR-ABL and prevents it from tagging the upper part of p27 lodged in the pocket of CDK2," he said. "This, in turn, prevents the lower part of p27 from swinging up into the pocket."

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

The other authors of the paper are M. Brett Waddell (St. Jude); Matthias Grimmler, Thomas Mund, Zoran Cilensek, Eva-Maria Keidel, Ludger Hengst (Max Plank Institute of Biochemistry, Martinsried, Germany) and Heidelinde Jakel and Michael Kullmann (Innsbruck Medical University, Innsbruck, Austria. Hengst is also at Innsbruck Medical University).

This work was supported in part by the National Institutes of Health, a Cancer Center (CORE) Support Grant, ALSAC, Regierung von Oberbayern (District Government of Upper Bavaria), the Max Planck Society and FWF (Fund for the Promotion of Scientific Research, Austria).

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org/.

St. Jude Children's Research Hospital
http://www.stjude.org/