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Gene knockouts reveal FoxOs' vital functions in cancer defense, health of stem cells

BOSTONIn an elegant, multiple-gene knockout experiment, a team of Boston scientists has discovered that a trio of molecules, called FoxOs, are fundamentally critical in preventing some cancers, maintaining blood vessel stability, and in keeping blood-forming stem cells healthy.

The discoveries reveal potential new targets for cancer drugs and could further research on stem-cell based therapies for degenerative diseases, said the researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital, who are jointly publishing two reports in the Jan. 26 issue of Cell.

The researchers at Brigham and Women's found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents' blood stem cells master cells that give birth to working blood cells while also renewing themselves divided too fast and "burned out," said Gary Gilliland, MD, PhD, who is senior co-author of the two papers with Ronald DePinho, MD, of Dana-Farber.

"If we didn't have these FoxO proteins to keep stem cells healthy, it is likely that we wouldn't be able to live for more than a few months," said Gilliland. Lead author of the stem cell paper is Zuzana Tothova, an MD-PhD student at Harvard Medical School working in Gilliland's lab.

In the companion paper, lead author Ji-Hye Paik, PhD, of Dana-Farber and colleagues from the DePinho lab report that the three FoxO molecules, known as transcription factors, normally function as tumor suppressors that override maverick cells threatening to grow too fast and form tumors. When FoxOs are eliminated, it may allow cancer to develop. The mice lacking FoxO proteins developed two types of cancer thymic lymphoma and hemangiomas, tumors caused by the uncontrolled growth of endothelial cells that form blood vessels.

DePinho's group identified two genes regulated by the FoxO molecules that might serve as
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Contact: Teresa Herbert
teresa_herbert@dfci.harvard.edu
617-632-4090
Dana-Farber Cancer Institute
25-Jan-2007


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