Life-or-death gene sheds light on lymphoma.
Michael O. Hengartner of the Massachusetts Institute of Technology in Cambridge told a conference of cancer researchers last week that the roundworm gene resembles a so-called proto-on-cogene known to cause follicular lymphomas in humans. And in the Oct. 9 SCIENCE, a research team led by Jean-Claude Martinou of the Centre Medical Universitaire in Geneva, Switzerland, reports that injections of the human protooncogene, called bcl-2, can prevent the normal death of cultured nerve cells starved of growth factors.
Hengartner discussed his results regarding ced-9, the roundworm equivalent of bcl-2, at the 16th Bristol-Myers Squibb Symposium on Cancer Research, held at the Fox Chase Cancer Center in Philadelphia. He and his colleagues found the ced-9 gene by studying mutant roundworms that develop with extra growths. Hengartner's group determined that these growths consist of cells that would normally die during embryonic development because the worm no longer needs them.
This process of programmed cell death, or apoptosis, occurs in most organisms. Without it, humans would retain the webbed fingers and toes they had as embryos. The same mechanism ensures that old, worn-out cells within the various organs of adults retire and die so that the body can replace them with fresh, lively cells that perform the same function.
"Programmed cell death is a way that multicellular animals have devised to properly get rid of cells that they do not want anymore," Hengartner says. The ced-9 gene regulates the process, he explains, by restraining two "suicide genes" that, when active, kill their own cell. A mutation that damages the ced-9 gene frees the suicide genes to spring into action, leading to cell death, he says.
The similarity between the roundworm gene ced-9 and the human gene bcl-2 may explain how a mutation involving bcl-2 causes human follicular lymphomas, Hengartner suggests. In many such lymphomas, complementary breaks in two different chromosomes allow bcl-2 to switch places with a member of the family of genes responsible for making antibodies. Because the antibody genes function continuously in most white blood cells, says Hengartner, the swap keeps ced-9 permanently turned on, letting some old white cells outlive their usefulness and proliferate as cancer.
"If you inhibit [the] process of cell death, you're going to get a tumor, because the cells are not going to stop dividing when they should," says Frank J. Rauscher III, a cancer researcher with the Wistar Institute in Philadelphia.
Research by Hengartner's team "really illustrates [that] what... some may feel are obscure [animal] systems may have absolutely critical relevance and application to what we see in human disease," says Robert L. Comis of the Fox Chase Cancer Center.
Martinou's group has added to Hengartner's cell-death findings by studying rat nerve cells grown in laboratory culture. They report that genetically engineered nerve cells containing extra copies of the bcl-2 gene live two to three times longer than normal nerve cells.
Martinou and his colleagues suggest that their finding might provide insights into degenerative diseases of the nervous system, such as Lou Gehrig's disease and Huntington's disease. Martinou has also found that nerves taken from aborted human fetuses contain active bcl-2 genes. This supports a widely held theory that embryos generate extra nerve fibers -- some of which later undergo programmed cell death -- to ensure that the nervous system develops the correct nerve connections.
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|Title Annotation:||roundworm gene may also shed light on other degenerative diseases|
|Article Type:||Brief Article|
|Date:||Oct 10, 1992|
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