NEW YORK, Oct. 11, 1996 -- Scientists at Memorial Sloan-Kettering Cancer Center have identified a human gene that arrests cell division in the laboratory and, when defective, may lead to the development of cancer. They reported the finding in the Oct. 11 issue of the journal Science.
The study suggests that if the gene's activity is blocked, cell division continues haphazardly and can lead to the formation of new cells that are missing chromosomes -- an event that is notoriously linked to tumor growth.
The researchers suspect that certain genetically unstable breast, ovarian, and prostate tumors may have defects in the gene, known as MAD2. The new discovery may open the door to finding more effective ways to treat such tumors.
"We think the MAD2 gene stops cells from dividing when doing so would leave the newly formed daughter cells without all the chromosomes they need to function properly," says Dr. Robert Benezra, an investigator in the Cell Biology and Genetics Program at Memorial Sloan-Kettering and the study's lead author.
MAD2 is the first human gene to be identified that serves as a checkpoint for cells to progress into the final stages of cell division. Until now, the only other checkpoint gene to be discovered was p53, which allows a cell to copy its DNA at an earlier phase in the cell cycle. Defects in the p53 gene are known to be involved in about half of all tumors.
The MAD2 gene allows a cell to commit to divide only after the gene checks to ensure that chromosomes, which contain DNA's genetic blueprint, are ready to separate normally to form two genetically identical cells.
"If MAD2 is defective and the checkpoint is challenged -- either by drugs or environmental stresses -- cell division can continue out of control and leave some new cells without a copy of each chromosome, which can lead to cancer," Dr. Benezra says.
The MAD2 checkpoint appears to plays an essential role in the cell cycle, Dr. Benezra says. After a cell's DNA is copied, each pair of the duplicated chromosomes is bound together at structures, called centromeres, that fit around each chromosome like a napkin ring. In order for a cell to divide, thread-like fibers must attach to each centromere and pull the chromosomes apart. That's where the MAD2 gene comes in.
The research suggests that MAD2 produces a protein that sits at the centromere of each chromosome and waits for the thread-like fibers to attach. If the fibers attach properly, cell division proceeds and each new cell gets a complete copy of the genetic blueprint of the original cell. But if the fibers fail to anchor to one of the centromeres, the corresponding chromosome pair can't separate normally and MAD2 puts the brakes on cell division.
Dr. Benezra speculates that MAD2 is only one of several genes involved in triggering this cell division checkpoint. In yeast, for example, six genes are known to exert their control over the checkpoint. Dr. Benezra, whose team discovered the MAD2 gene by accident, also is investigating a second human gene suspected of being involved in the checkpoint.
The new research may help to improve future treatment options for cancer patients. In the study, the researchers identified a human breast tumor cell line that is sensitive to the cancer drugs taxol and nocodazole. The drugs, called spindle inhibitors, block the formation of the thread-like fibers that pull chromosomes apart during cell division.
After the researchers treated the breast tumor cell line with nocodazole, the cells continued to undergo cell division, which suggests the cells may be defective in the checkpoint. When the investigators looked further, they confirmed their suspicion -- the cell line had low levels of MAD2 expression compared to control cells that were resistant to both drugs.
The drugs may be especially effective in the treatment of tumors with a defective checkpoint, Dr. Benezra says. That's because the drugs, coupled with the faulty checkpoint, so completely dismantle a cell's ability to divide normally that it leads a cell to commit suicide, he adds. In the future, it may be possible to completely inactivate the checkpoint in tumor cells and then treat those tumors with spindle inhibitors.
The research is supported by grants from the National Science Foundation and the National Cancer Institute.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its long, distinguished history, the Center has played a leadership role in defining the standards of care for patients with cancer. Memorial Sloan-Kettering was recently named the nation's best cancer center for the fourth consecutive year by U.S. News & World Report.