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Apoptosis - The Regulatory Mechanism

genetic cell ced proteins cells

The cellular mechanisms that regulate and cause apoptosis were first elucidated by genetic studies of the roundworm, Caenorhabditis elegans. Normally, in the development of a C. elegans worm, one out of every eight body cells produced is eliminated by programmed cell death. By studying mutants in which either too many or too few cells died, worm geneticists identified many of the proteins that control apoptosis. Subsequently, the critical medical relevance of apoptosis became clear when biologists discovered that mammals contain many of the same genes that control apoptosis in worms. More strikingly, they found that many of these genes were mutated in tumors from cancer patients. Other genes often found to be mutated in cancers are those which regulate the cell cycle, which is the complex set of processes controlling how and when cells divide. These two findings led cancer researchers to recognize that cancer, a disease of uncontrolled cell proliferation, can result either from too much cell division or not enough apoptosis. Because of this important finding, apoptosis has become the subject of intense medical research, and molecules that regulate apoptosis are being studied as potential targets for anti-cancer drug therapies.

A cell can be triggered to undergo apoptosis either by external signaling molecules, such as so-called "death activator" proteins, or through molecules that reside within the cell and monitor events that might commit the cell to suicide, such as damage to DNA. There are several biochemical pathways that lead to apoptosis. One of the major pathways involves inducing mitochondria to leak one of their proteins, cytochrome c, into the cystosol. This in turn activates a set of related proteases (enzymes that degrade proteins) called caspases. Ultimately, the caspases degrade proteins in the cell and activate enzymes that degrade other cell constituents, such as the DNA. Cells undergoing apoptosis exhibit characteristic morphological and biochemical traits, which can be recognized by microscopic examination or biochemical assays. Apoptosis can occur in as little as twenty minutes, after which the cell "corpse" typically becomes engulfed and completely degraded by neighboring phagocytic cells that are present in the tissue and attracted to the apoptotic cell.

Paul J. Muhlrad

Bibliography

Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.

Nature 407, no. 12 (Oct., 2000). (Issue devoted to review articles on apoptosis).

Internet Resource

The WWW Virtual Library of Cell Biology. "Apoptosis." <http://vlib.org/Science/Cell_Biology/apoptosis.shtml>.

APOPTOSIS GENES IN C. ELEGANS

Much of our understanding of what causes apoptosis comes from genetic studies in Caenorhabditis elegans. Several cell death proteins (CED) proteins were identified in C. elegans by studying apoptosis-defective mutants. The main executioner is CED-3, a caspase, which becomes activated by CED-4, another caspase. The central guardian protecting cells against apoptosis is CED-9, which inhibits the actions of CED-4 and CED-3. CED-9 has a mammalian homolog, called BCL-2, which serves a similar role in mammals.

Caspase inhibitors are being investigated as a possible means to slow the progress of Huntington's disease, a degenerative brain disease.

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