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September 20, 2001

Gene that Prevents Tumor Growth Has Second Major Function In Carrying Messages From Circadian Clock, Penn Scientists Find

PHILADELPHIA, Pa. -- Scientists have long known that the gene Nf1 is so important to development that when it is missing the condition known as Neurofibromatosis results, causing tumors and sometimes leading to cancer before the patient reaches adulthood.

Now researchers have discovered that the Nf1 gene serves a second major purpose: It is also necessary for circadian rhythm. The body can't maintain its rest-activity cycle without it.

"There have been a lot of anecdotal reports by physicians that many patients suffering from neurofibromatosis also suffer from sleep disturbances. But this is the first time someone has definitively linked Nf1 to the circadian system," said Julie Williams, PhD, first author of the study by scientists at the University of Pennsylvania School of Medicine.

Their finding, to be published Friday, Sept. 21, in the journal Science, represents a major advance in understanding the body's complex circadian mechanism. It moves the research beyond the question of what constitutes our biological clock, and how it responds to light, to the more specific question: How does it actually regulate changes within the body?

Williams and her colleagues found that in the absence of the Nf1 protein, the body is unable to keep time. Although their research relied on the Drosophila fly model, the Penn scientists were also able to establish that the signaling pathway triggered by Nf1 in the fly is directly analogous to the Nf1 pathway in mammals.

"Our work shows that when Nf1 affects circadian rhythm in flies, it uses the same mechanism that is present in humans, which is the Ras/Mapk pathway. This validates the fly as the model to study this illness," said Amita Sehgal, PhD, who directed the study.

"You can think of it like an electric circuit," Sehgal said. "We have the clock. Now we have identified another part of the circuitry. We've identified a protein that 'works' in the circuitry. This will allow us to determine where some of the wires go.

The researchers believe that is important because it provids a handle on the signals that transmit time-keeping cues from the clock to other parts of the body. "We've found that Nf1 affects the circadian rhythm of the 'rest' phase in the cycle, but it doesn't affect the clock itself," said Sehgal. "The clock is keeping time-but it can't send the message affecting 'rest' without NF1," Sehgal said.

The research was funded by the Howard Hughes Medical Institute, NIH, Neurofibromatosis Foundation, American Cancer Society, and U.S. Army Medical Research command.

Others who participated in this study are: Henry S. Su, PhD; Jeffrey Michael Field, PhD, both Penn scientists, and Andre Bernards, PhD, of Massachusetts General Hospital Cancer Center in Boston.

 


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