November 14, 1997
Hughes Researchers Discover Key Component of Cell Death Pathway
The puzzle of how cells commit suicide has finally been solved,
yielding a solution that may translate into effective drugs to treat
cancer and other diseases.
"This research may provide new targets for therapy that blocks or
initiates cell death," said Xiaodong Wang, a Howard Hughes Medical
Institute investigator at the University of Texas Southwestern Medical
Center at Dallas. Wang led a research team that discovered the protein
that initiates the final stage of cell death, known as apoptosis. The
finding, reported in the November 14 issue of the journal Cell,
is the third molecule that Wang has identified this year as vital in
the cascade of events that leads to apoptosis.
“We now begin to understand how cell death is initiated, which is really the middle of the pathway”
Xiaodong Wang
This model is likely to be relevant to all organisms, said Wang.
"This appears to be one of the global mechanisms of apoptosis," he
said.
Paradoxically, cell death is important in the early development of
many organisms because it helps to generate the proper number of cell
types in the right places. If apoptosis doesn't occur, cancer or
autoimmune diseases can arise. Conversely, neurological disorders and
paralysis due to disease or trauma can cause too many cells to die. So
drugs that accelerate or prevent apoptosis could be helpful in treating
a wide range of diseases.
At the cellular level, apoptosis occurs quickly and leaves no
traces: A cell's nucleus condenses and fragments, the cell shrivels,
and then is quickly engulfed and digested by macrophages or other
neighboring cells. Once inside the macrophage, the dying cell is
quickly disassembled and its components recycled.
The cell's intrinsic death program was first discovered and
described in nematode worms by Hughes investigator H. Robert Horvitz at
MIT and a number of other researchers. The worm generates about 1,000
somatic cells in the course of development, but 131 of those cells are
programmed to die. Researchers have subsequently shown that the cell
death program and the molecular henchmen that deliver the death
sentence are highly conserved in organisms as diverse as worms and
humans.
Three genes, ced-3, ced-4, and ced-9 encode proteins
that execute the apoptopic program in nematode worms (ced stands for
"cell death abnormal.") Ced-9 prevents cell death, while ced-3 and
ced-4 promote death. Wang and others have been searching for the human
homologues of the worm genes. The Bcl-2 family of proteins contains the
mammalian relatives of ced-9; and ced-4 is homologous to the recently
identified human protein, Apaf-1. The mammalian ced-3 homologue is
caspase-3.
Wang's two-year search for other members of the cell death pathway
has paid off handsomely. In February, his team discovered that Bcl-2, a
protein in the outer membrane of mitochondria, the cell's principal
energy source, prevents the release of cytochrome c, a carrier in the
cell's energy chain (February 20, 1997, Science). This outflow
of cytochrome c from the mitochondria signals the beginning of cell
death. The discovery connected Bcl-2 —previously shown to be
involved in cell survival by Hughes investigator Stanley Korsmeyer at
Washington University— to cytochrome c, a chemical trigger of cell
death. And in August, Wang's group published a paper in Cell
linking cytochrome c to Apaf-1. (August 8, 1997, Cell).
In the latest paper, Wang's team uses human breast cancer and
cervical cancer cells to purify Apaf-3. They found that Apaf-3 binds to
Apaf-1 in the presence of cytochrome c and dATP or ATP, which carries
energy from the mitochondria to all parts of the cell. This complex of
molecules then turns on the protease caspase-3, the final trigger that
initiates cell death.
According to Wang, such detailed knowledge of the apoptotic pathway
gives scientists better targets for their efforts to switch the cascade
on to destroy cancer cells or off to prevent cell death due to strokes,
heart attacks or neurological diseases.
"We now begin to understand how cell death is initiated, which is
really the middle of the pathway," said Wang. "Now we plan to look at
the beginning and end of the process to determine what triggers these
events and understand how the cell breaks up."
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