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Nitric Oxide Found to Control Cells by Turning on Genes: Suggests New Role in Health and Disease

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Duke Health News 919-660-1306

DURHAM, N.C. -- In a discovery that defines a new message
system inside living cells, a team of researchers led by Duke
University Medical Center reports finding that the chemical
nitric oxide is a universal signaling molecule that can control
basic life processes down to the level of the gene, the master
plan of a cell.

The study findings, published in the Sept. 6 issue of the
journal Cell, describes an entirely new cellular signaling
mechanism -- the attachment of nitric oxide (NO) to a key
portion of a protein called a thiol -- that can directly
activate genes. The work was funded by the National Heart, Lung
and Blood Institute, a division of the National Institutes of
Health.

The researchers theorize that the process of flagging
proteins with NO to activate them may prove to be as
fundamental a biological process as flagging proteins with
phosphate, a process now understood to be the primary on-off
switch for thousands of proteins that control life
processes.

Although the discovery was made in bacteria, the team
believes that human cells also use NO molecules as a genetic
signaling mechanism.

"It appears that life uses NO ubiquitously," said the
study's leader, Dr. Jonathan Stamler, a cardiologist and
pulmonologist. "Knowing that NO compounds have the ability to
turn genes on is a phenomenal understanding that may lead to a
new chapter of research and possible therapeutic uses."

The finding ties together the mountains of scientific
studies in recent years linking NO with everything from blood
vessel dilation to neurotransmission in the brain to intestinal
contraction to penile erection. "Virtually everywhere
scientists look in the body, they find NO has a role," Stamler
said. "This study shows why. NO influences myriad body
functions because NO is a universal signal."

The body keeps NO, which is toxic in excess, in balance by
sensing how much NO is present and turning genes on and off to
keep NO in equilibrium. If this equilibrium is upset, Stamler
theorizes, it may lead to a number of diseases that have
recently been associated with NO, including cancer, stroke,
hardening of heart arteries, infectious disease, and
arthritis.

The scientists say that an immediate application from the
research may be a new way to disarm invasive bacteria that have
become resistant to antibiotics -- a major problem in the
treatment of infections, especially in hospital settings.

Other contributors to the work include Alfred Hausladen, a
Duke biochemist, and Christopher Privalle and Teresa Keng, two
former Duke researchers who are now scientists at Apex
Bioscience Inc., Research Triangle Park, N.C. Joseph DeAngelo,
director of research at Apex, also collaborated on the
project.

This is the second recent discovery Stamler has made in NO
research. Earlier this year, he found that an NO compound,
combined with hemoglobin, is a major regulator of gas exchange,
as well as blood pressure, in the circulatory system. That work
was published March 21 in the British journal Nature.

The current discovery was made when the researchers were
studying why some bacteria escape attack by immune system cells
called macrophages, which are designed to disable and devour
them. The question is of increasing importance in acute health
care.

When bacteria invade the body, the immune system floods the
bacterial cell with noxious oxygen and nitrogen-free
radicals.

The researchers found that when NO enters a bacterium, the
NO attaches to a particular place on proteins called a thiol, a
protein subunit that contains sulfur. The NO-thiol coupling
forms a new NO-compound called SNO (for S-nitrosothiol). SNOs
are souped-up cousins of NO molecules, and they have a wider
range of functions.

To defend themselves, bacteria deploy an army of small thiol
mops that sop up the SNO barrage and then break SNO down into
harmless compounds. This is a bacterium's first line of
defense.

If too much SNO gets in, it disables the bacteria by
damaging key proteins the bacteria need to survive. While the
bacteria are busy trying to repair themselves, the macrophages
can attack and destroy them.

But the scientists discovered that the bacteria have an
additional defense system. SNO compounds also attach to a
transcription factor, a protein that finds specific genes on
the bacterial genome and activates them. The genes, in turn,
are translated into proteins whose job it is to break down the
excess SNO, rendering it harmless.

In this way, bacteria have evolved an ingenious second line
of defense against an SNO attack, Stamler said in an interview.
"The bacteria offer SNO a target, which turns out to be a
genetic switch that leads to its own destruction." he said.
"The moment SNO enters a bacterium, a race is on as to whether
it will defend itself quickly enough to evade the immune
attack, or whether the SNO will win by quickly disabling the
cell, making it vulnerable to a macrophage attack. In some
cases, then, the bacterium wins, forming resistance to an
immune system attack."

The findings offer both practical and profound implications,
Stamler said.

The immediate benefit of the research is to suggest a way
that new antibiotic drugs might be developed, said Hausladen,
the study's first author. These drugs could plug up the
transcription factor, known as OxyR, preventing it from being
switched on, or they could bind to and deactivate the proteins
that are produced to break down SNO. "This would be a novel way
to disarm bacteria that has never been exploited," Hausladen
said.

The actions of NO in this experiment also resemble the
process by which oxygen affects cell health and disease, the
scientists say.

"Now we have demonstrated that an NO group, attached to a
thiol within a cell, has regulatory function," Stamler said.
"There has been growing evidence that NO does its work in the
body by signaling genes, but no one has found proof before
this."

Both oxygen and NO are vital to life processes, but too much
of either can damage cells. To keep the amount of oxygen and NO
in balance, cells have built-in systems to eliminate the
excess. One way to do that is to have transcription factor
sensors that get turned on when too much oxygen or NO is
present.

In fact, bacterial cells attempt to control both excess
oxygen and excess nitrogen with the same OxyR transcription
factor.

In human cells, constant vigilance against excess oxygen and
NO takes a toll over time. When the system is out of balance,
perhaps when a transcription factor is mutated, disease can
result, the scientists say.

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