February 25, 2000
"Messenger of Death" Molecule Identified
Researchers have found that a signaling protein that is part of the
cell's natural suicide machinery may act as a "messenger of death" that
travels to the cell's nucleus to execute the process of programmed cell
death.
Their finding adds an important piece to the puzzle of how
malignant, malfunctioning or unneeded cells are instructed to commit
suicide, or apoptosis, during an organism's development.
“Misregulation of programmed cell death can play a central role in certain cancers, autoimmune diseases and neurodegenerative diseases.”
H. Robert Horvitz
While the scientists emphasize that there is much more work to be
done, they say that studies of the proteins that cause apoptosis might
offer targets for drugs that can prevent cell death related to heart
attacks, strokes, or Alzheimer's disease.
Led by HHMI investigator H. Robert Horvitz at MIT, the research team
reported their discovery in the February 25, 2000, issue of
Science. The team also included scientists from the Max Planck
Institute for Biological Chemistry in Germany and the Hebrew University
in Jerusalem.
"Programmed cell death is a key mechanism for regulating cell
numbers and connections and for sculpting tissues," said Horvitz, who
was among the pioneers in discovering the process. "Its misregulation
can play a central role in certain cancers, autoimmune diseases and
neurodegenerative diseases. We now know many of the molecules that
control programmed cell death. Our new finding offers insights as to
how one of these key molecules works."
The scientists conducted their research using the transparent
nematode worm, Caenorhabditis elegans, long employed as a model
to study apoptosis. The tiny worm contains exactly 1,090 cells, of
which 131 undergo apoptosis, most during embryonic development.
Previous research by Horvitz's team had shown that four proteins
—EGL-1, CED-9, CED-4, and CED-3 —play a central role in the
apoptotic machinery. CED stands for "cell death abnormal."
EGL-1 initiates apoptosis by inhibiting the normal restraining
action of CED-9 on CED-4. Once unleashed from its restraints, CED-4
then triggers CED-3, which is a highly destructive protein-destroying
enzyme that wreaks havoc on a cell's structures.
"Genetic studies of mutant worms that lacked one or another of these
proteins had shown that they affected one another. We wanted to see
whether and where they interact in the cell," said HHMI predoctoral
fellow Bradley Hersh. Thus, said Hersh, he and his colleagues used
antibodies that tagged each protein involved in apoptosis to reveal
their cellular locations. Their experiments involved eliminating one or
another of the signal proteins and studying the effects on protein
localization.
"Our initial experiments showed that both CED-9 and CED-4 are
localized to mitochondria," said Hersh. Mitochondria are the
energy-producing powerhouses of the cell. Some scientists believe that
mitochondria are the natural centers for the "sensors" that trigger
programmed cell death, since malfunctioning mitochondria seriously
compromise cell viability.
"Once we knew where these two proteins reside normally, the natural
thing to do was look at how they affected the localization of one
another," said Hersh. "We were surprised to find that that when we
eliminated CED-9, CED-4 localization changed to the nucleus. After all,
the mammalian counterpart of CED-4 is found mainly in the cytoplasm,
and there was no indication that it would go to the membrane
surrounding the nucleus."
Still mysterious, say Horvitz and Hersh, is how CED-4 reaches the
nuclear membrane. They are studying CED-4 mutants that fail to reach
the nucleus. Such mutants might reveal clues to the transport process
and its importance in cell death.
While the discovery of CED-4's translocation to the nuclear membrane
is a basic one, it could have eventual clinical implications, said
Hersh.
"If CED-4 translocation is required for activation, then inhibiting
the translocation of a human counterpart of CED-4 might block cell
death in such cases as ischemic injury in heart attacks or strokes," he
said. "Also, in Alzheimer's disease, apoptosis may be central to the
death of neurons, and blocking such a CED-4-like molecule might
preserve brain tissue." However, he continued, "we still don't know
enough about this process to know whether inhibiting a CED-4-like
protein, or translocation in the cell, will be possible. At this point,
inhibiting human CED-3 counterparts, known as caspases, seems the most
promising approach to blocking apoptosis, since these caspases have an
established biochemical activity for which inhibitors have already been
identified."
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