How cells prevent suicide

January 23, 1997

Researchers have shown that a mysterious protein crucial to the survival of cells throughout the body is able to form a channel through the internal membranes of cells, and thus may perform the vital function of selectively passing atoms or electrically charged ions between the cell's compartments. The finding, reported in the January 23, 1997 issue of Nature, provides a clue as to how a family of proteins works to hold in check the suicide of needed cells. The genes for these same proteins, when overexpressed, can also block the die-off of unwanted cells, which can lead to tumors and autoimmune diseases.

The protein, called Bcl-xL, is one of several proteins known to play a role in programmed cell death or apoptosis—a tightly controlled process necessary for normal growth and development. In apoptosis, the targeted cell's genetic material disintegrates as it withers and dies. Each cell in the body, in effect, carries a dagger with which to commit suicide when told it is irretrievably damaged, say by a virus or radiation, or is no longer needed. A controlled die-off of cells is what shrinks swollen lymph glands back to normal after a cold subsides.

The Bcl-type proteins, found in nearly all tissues and in organisms from the lowest invertebrates to humans, are immortality factors that cause lymph nodes to grow abnormally in the B-cell lymphoma for which they are named. But they had also been shown to be essential to embryonic development.

"Without the Bcl-xL gene to tell cells to survive in developing organs, you don't get viable organs," says Craig Thompson, MD, director of the University of Chicago's Gwen Knapp Center for Lupus and Immunology Research and an investigator in the university's Howard Hughes Medical Institute, who is senior author of the new study. “If you can't regulate programmed cell death, you can't even develop into an organism. You die before you get there."

The challenge has been to find a function for the Bcl-xL protein. A clue was provided last year, when Thompson's group with collaborators at Abbott Laboratories determined the precise three-dimensional shape of the Bcl-xL molecule. By comparing it to the database of all known protein structures, they found it most closely resembles an unexpected candidate—diphtheria toxin and other proteins that punch holes in cell membranes. It was also shown by other researchers that the Bcl family of proteins reside on the membranes that divide the compartments within the cell.

Now Dr. Thompson's group and his Abbott collaborators have teamed up with electrophysiologists from Loyola and Purdue universities to show that Bcl-xL can insert itself into an artificial membrane and allow ions to pass through the normally impermeable barrier.

"For the first time, we can identify something these proteins actually can do, so that's a potential lead into how they regulate cell survival. But there's not a proof yet that this is the function that contributes to their ability to regulate survival," Dr. Thompson said. "It's attractive though, because one thing the cell has to do is coordinate all the events that go on inside. It has to have an energy source, it has to transcribe new genes in the nucleus, and those genes have to be made into new proteins. The three places that Bcl-type proteins are found are ideal places to communicate information between the separate compartments in which these activities take place."

Other authors on the Nature paper include Andy Minn, an MD/PhD student in Thompson's laboratory, Patricio Velez and Michael Fill at Loyola, Heng Liang, Stephen Fesik and Steven Muchmore at Abbott Labs, and Sharon Schendel at Purdue.

The research was funded by the National Institutes of Health.

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