Genetic discovery in fruit flies may open new avenues for understanding cancer growth in humans

appropriate gene silencing is thought to account for various sex-linked genetic disorders, in which the affected genes are located on the X chromosome. Such developmental abnormalities, which nearly always affect males, include xeroderma pigmentosum (a rare, inherited skin disease that causes extreme sensitivity to sunlight and increased risk of skin cancer), color blindness and hemophilia.

Malfunctions in gene silencing also have been implicated in several human cancers, including acute myelogenous leukemia, colon cancer and several forms of breast cancer.

Sir2 is an attractive drug target because it has been found to modulate the function of p53, an important tumor-suppressor protein which, when defective, can increase cancer risk in humans. One drug under investigation at Fred Hutchinson, called Splitomicin, is a potent inhibitor of gene silencing. It works by interfering with Sir2's ability to cloak the chromosome in proteins that shield it from factors needed for activation. The compound is highly specific, halting the function of Sir2. Such precision is an attractive feature in drug design because it increases a drug's effectiveness and decreases its side effects. Fred Hutchinson researchers scientifically reported the drug's discovery last December and the center has filed patent protection for it.

In the Cell paper, Parkhurst and Rosenberg report that the drug, which already has been shown to reverse global gene silencing in yeast, also works in fruit flies.

"With fruit flies, we now have a multi-cellular model system that is more complex than yeast that will allow us to study all of the functional components of the pathway that are required for the drug to work," Parkhurst said. "Now that we know the drug works on fruit fly Sir2, this opens up all kinds of possibilities that we wouldn't have thought to try before." For example, this finding now hints at the drug's potential for treating diseases that result from the faulty regulation

Contact: Kristen Woodward
Fred Hutchinson Cancer Research Center

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