April 23, 1999
Researchers Discover Cell Death Switch
There are times when a cell’s "decision" to die is a good
idea. During viral infection, for example, cell death can deprive an
invading virus of the infrastructure it needs to replicate and infect
other cells. Scientists have learned a great deal about this orderly,
programmed cell death—which is known to scientists as
apoptosis—but the mechanisms that turn on the process have
remained largely hidden from researchers.
Researchers at the Howard Hughes Medical Institute (HHMI) at Duke
University in collaboration with scientists at the Dana-Farber Cancer
Institute have now found that nitric oxide (NO), a well-studied
molecule implicated in a host of communication pathways in and between
cells, is also a switch that controls whether cells live or die.
“If you block nitric oxide production within the cell, you make the cell more susceptible to cell death. And if you add it back, you prevent cell death.”
Jonathan S. Stamler
The discovery, which is reported in the April 23, 1999, issue of the
journal Science, reveals a potential therapeutic target for a
host of ailments, including cancer, liver failure and diseases of the
immune system, heart and brain.
"Nitric oxide is among the most pervasive signaling molecules in
biology," said Jonathan S. Stamler, an HHMI investigator at Duke
University. "It binds to proteins and regulates their activity, and
there is increasing evidence that it regulates cell growth, cell
differentiation and now the death program of cells."
Stamler and his colleagues found that NO molecules occupy a critical
site on the enzyme caspase, a molecular "executioner" within human
cells. When occupying this site, NO effectively plugs a communication
pathway that activates caspase and triggers cell death.
"We showed that nitric oxide sits on the site and keeps the enzyme
inactive," said Stamler. "Conversely, the nitric oxide is removed in
cells programmed to die. Simply put, if you block nitric oxide
production within the cell, you make the cell more susceptible to cell
death. And if you add it back, you prevent cell death."
Apoptosis can be triggered through a biochemical chain of events
known as the Fas pathway. When activated, the Fas pathway initiates a
cascade of signals within the cell that ultimately turns on caspase.
When NO occupies the site on caspase, however, the death message is
blocked. Fas somehow manages to pop the nitric oxide off the cells that
are programmed to die.
The discovery of the NO switch, said Stamler, reinforces research in
animals that shows that it may be possible to reverse heart failure,
liver damage or arteriosclerosis by interfering with apoptosis. It may
be possible, for example, to construct synthetic molecules that can act
within cells to block or inhibit the cell death that occurs in heart
and liver disease. "We’d like to think modulation of the nitric
oxide system can be used for therapeutic gain," he said.
Similarly, says Stamler, the NO switch could be used to prevent
tumor formation or progression. "In cancer cells, where nitric oxide is
overproduced, for example, we should be able to take out nitric oxide
and promote cell death." One catch, Stamler added, is that scientists
do not yet know how to remove NO from its position on the caspase
enzyme.
It may be possible to identify chemicals that knock nitric oxide off
its caspase perch, he said. "There must be things that remove the
nitric oxide molecule, but we don’t yet know what they are."
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