Researchers Discover Cell Death Switch

April 23, 1999

April 23, 1999
–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.

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

Howard Hughes Medical Institute

Related Cell Death Articles from Brightsurf:

Cell death in porpoises caused by environmental pollutants
Environmental pollutants threaten the health of marine mammals. This study established a novel cell-based assay using the fibroblasts of a finless porpoise stranded along the coast of the Seto Inland Sea, Japan, to better understand the cytotoxicity and the impacts of environmental pollutants on the porpoise population.

Gold nanoparticles to save neurons from cell death
An international research team coordinated by Istituto Italiano di Tecnologia in Lecce (Italy) has developed gold nanoparticles able to reduce the cell death of neurons exposed to overexcitement.

New light shone on inflammatory cell death regulator
Australian researchers have made significant advances in understanding the inflammatory cell death regulatory protein MLKL and its role in disease.

Silicones may lead to cell death
Silicone molecules from breast implants can initiate processes in human cells that lead to cell death.

New players in the programmed cell death mechanism
Skoltech researchers have identified a set of proteins that are important in the process of apoptosis, or programmed cell death.

Tumors hijack the cell death pathway to live
Cancer cells avoid an immune system attack after radiation by commandeering a cell signaling pathway that helps dying cells avoid triggering an immune response, a new study led by UTSW scientists suggests.

How trans fats assist cell death
Tohoku University researchers in Japan have uncovered a molecular link between some trans fats and a variety of disorders, including cardiovascular and neurodegenerative diseases.

Bacteria can 'outsmart' programmed cell death
To be able to multiply, bacteria that cause diarrhoea block mediators of programmed cell death, a new study in 'Nature Microbiology' shows.

Cell death or cancer growth: A question of cohesion
Activation of CD95, a receptor found on all cancer cells, triggers programmed cell death -- or does the opposite, namely stimulates cancer cell growth.

Cell death blocker prevents healthy cells from dying
Researchers have discovered a proof-of-concept drug that can prevent healthy cells from dying in the laboratory.

Read More: Cell Death News and Cell Death Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to