Scientists at Jefferson Medical College of Thomas Jefferson University in Philadelphia appear to have an important clue to the workings of a gene that normally protects against cancer. Ultimately, by understanding how both the normal and the damaged gene work, scientists may be able to find ways to interfere with the development of cancer.
Charles Brenner, Ph.D., assistant professor of microbiology and immunology, and a member of Jefferson's Kimmel Cancer Center, and his colleagues at the University of Texas in San Antonio, and at the University of Sheffield in England, have distinguished between potential mechanisms by which the FHIT gene works in preventing cancer development.
A report of the researchers' work appears May 12 in the Proceedings of the National Academy of Sciences.
Dr. Brenner and his colleagues used a combined genetic, biochemical and crystallographic approach to gain information about the function of the tumor-suppressor protein, Fhit, the product of the FHIT gene.
According to Dr. Brenner, Fhit is "encoded in the most fragile site of the human genome. The FHIT gene is frequently inactivated early in the development of cancer, especially in lung cancer."
Dr. Brenner and his co-workers sought to understand how the Fhit protein suppresses tumor formation. "We knew that the Fhit protein is an enzyme that binds and cleaves an unusual class of nucleotides in the cell, called ApppA," he explains. "We wanted to determine if the important function of Fhit was to cleave ApppA or signal the presence of this compound in the cell in order to put the brakes on cell growth." Tumors form when the Fhit protein is absent.
New experiments showed that altered forms of the Fhit protein that bind but don't cleave ApppA are actually still working in tumor suppression. "That excluded the idea that the important thing that Fhit does in the cell is to cleave ApppA," he says. However, Dr. Brenner says that because the altered Fhit binds the compound but can't cleave it, "the function of Fhit is to signal the presence of the compound to other proteins in the cell."
The work suggests that ApppA is an "alarmone, a signal that cells use to control the proliferation rate or to commit suicide." One of the ways cells control their growth is by programmed cell death.
"The genetic and biochemical work suggests that the active form of Fhit is the Fhit-ApppA complex, which is produced in the cell in response to elevated levels of ApppA," he adds. Dr. Brenner and his colleagues then performed X-ray crystallography, which provided the structure of the Fhit-ApppA complex, the apparent active, signaling form of Fhit.
"The ultimate aim is to follow the entire pathway from the initiation of the ApppA signal to the ultimate events that arrest the growth of cells and keep them from forming tumors," he says. "We'd like to identify steps in that cellular pathway in which we can intervene and restore a Fhit-like signal in the absence of Fhit or to kill the cells that are missing Fhit."
In February 1996, a team of scientists led by Kay Huebner, Ph.D., professor of microbiology and immunology at Jefferson Medical College and the Kimmel Cancer Center, and Carlo Croce, M.D., professor of microbiology and immunology and director of the Kimmel Cancer Center, announced that they had identified the FHIT gene. of the FHIT gene inactivation is an early event in the development of several types of cancer.
Dr. Brenner's work is funded by the National Cancer Institute, the March of Dimes Birth Defects Foundation, the Burroughs Wellcome Foundation and the Arnold and Mabel Beckman Foundation.
Journal
Proceedings of the National Academy of Sciences