| September 20,
Gene that Prevents Tumor Growth Has
Second Major Function In Carrying Messages From Circadian
Clock, Penn Scientists Find
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
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
"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.