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New Components of Machinery that Carries Genetic Information from Nucleus

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Duke Health News 919-660-1306

DURHAM, N.C. -- Researchers have reported discovering the
first elements of what is apparently a molecular signaling
pathway important for regulating how genetic information leaves
the nucleus to begin its working life as a blueprint for the
cell.

According to the scientists, their finding represents an
intriguing new role for a signaling molecule, derived from
inositol, in the cell.

In an article in the July 2 Science, Duke University Medical
Center pharmacologist John York and his colleagues reported
studies in yeast that revealed the presence of enzymes called
kinases - enzymes that add phosphates to inositol to make them
into signals that trigger the export of messenger RNA from the
cell nucleus.

Messenger RNA (mRNA) is the molecule that, when copied from
DNA genes in the nucleus, carries genetic information into the
cell where it is used to build proteins.

Co-authors on the article are Audrey Odom, also of Duke, and
Robert Murphy, Eric Ives and Susan Wente of Washington
University School of Medicine. York is an assistant professor
of pharmacology and cancer biology, and of biochemistry. Odom
is a graduate student in the Medical Scientist Training
Program. The research was sponsored by the Burroughs Wellcome
Fund, the National Institutes of Health and the American Cancer
Society.

While York emphasizes that the discovery is very basic in
nature, and was made using yeast, such fundamental knowledge
invariably contributes to understanding and treatment of human
disease, he said. Particularly important, he emphasized, is
that inositol signaling is critical to the machinery of living
cells, and many of its components are conserved all the way
from yeast to humans.

Inositols had already been suspected of being major
signaling molecules in the cell, because some 20 different
inositols had been discovered with varying numbers and
arrangements of phosphates attached, like a multitude of keys
with slightly different shapes. However, researchers still do
not understand where and when the cell uses these molecular
keys, and which locks they open.

The most well-known inositol, IP3, has three phosphates
attached, and is produced in the cell in response to stimuli,
via the action of a key enzyme called phospholipase C. IP3 is
known to be critical for triggering the release of calcium,
which in turn triggers other cell processes.

However, York and his colleagues to their surprise had found
that IP3 apparently has yet unknown extended signaling roles,
produced when additional phosphates are added to produce IP4,
IP5 and IP6 in the cell. Production of these IPs also depends
on phospholipase C activity in cells.

The latest research began when York contacted Wente, after
learning through colleague Jeremy Thorner of the University of
California-Berkeley that Wente had discovered a link between a
phospholipase C and an essential factor GLe-1 that is essential
for transporting mRNA out of the nucleus. Of particular
interest was that Wente had also discovered that two other
genes of unknown function also linked to GLe-1.

York theorized that the other two genes might be the
blueprints for two new kinases responsible for adding
phosphates to IP3 on the way to producing IP6.

"It was easy to test this hypothesis," said York. "We just
introduced radio-labeled inositol into yeast strains mutated to
lack the genes for one or the other of the suspected kinases.
Depending on the kinase blocked, we expected to see buildup of
either IP3 or IP5, with no IP6 in any case." Sure enough, said
York, the experiments indicated that the mysterious genes coded
for kinases, or at least their regulators, transformed IP3 to
IP4, and IP5 to IP6.

According to York, still to be determined is whether IP6
directly or indirectly affects the transport of mRNA from the
nucleus. IP6 may merely regulate the "gatekeeper" -- called the
Nuclear Pore Complex -- a huge protein machine that controls
the passage of mRNA and other substances out of the nucleus.
Or, IP6 may directly affect the protein "package" that carries
mRNA through the Nuclear Pore Complex.

Especially intriguing, said York, is that inositol signals
are not absolutely necessary for mRNA to leave the nucleus,
except at high temperatures.

"One idea is that this process is involved only in transport
of specific genes that are needed to help cells adapt to
stress, such as heating," he said.

Future studies will aim at identifying the protein that is
the target of the IP6 signal and how it affects that protein to
act as a switch. More broadly, the discovery of the two kinases
has helped open up an important new research pathway,
emphasized York.

"This discovery really challenges the idea that IP3 was the
sole signal coming from this pathway," he said. "In fact, we
know now it's not. Now we know that while this pathway begins
by affecting calcium, it ends with the export of mRNA from the
nucleus as mediated by IP6. We now want to find out what are
the signaling roles of each molecules along this pathway, and
in fact whether there's a signal after IP6."

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