BOSTON--February 24, 1998--Researchers at Harvard Medical School have identified four human genes that serve a critical role in cell division. The findings provide a new target for anticancer agents, which may result in fewer therapeutic side-effects.
Hongtao Yu, a postdoctoral fellow in the laboratory of Marc Kirschner, the Carl W. Walter professor of cell biology at Harvard Medical School, and his colleagues used frog (Xenopus) protein sequences as a guide to identify the remaining four human genes in the eight-unit anaphase-promoting complex (APC). The APC's critical role in cell division makes it a perfect target for the fight against cancer, in which cells escape regulation and divide uncontrollably. The findings are published in the February 20 Science.
APC proteins are activated as the cell progresses through mitosis, but as yet, Kirschner and Yu do not know exactly how they are regulated. However, uncertainty about APC's regulation does not diminish the potential of this multi-subunit complex for anticancer therapeutics. With its seminal role in mitosis, the APC seems to be a perfect site to halt cell division. Like the anticancer drug Taxol that also disrupts mitosis, the advantage with an APC inhibitor would be preferential delivery to rapidly dividing tumor cells. "A lot of normal cells are just not dividing at all," says Yu. These law-abiding noncancerous cells would be invisible to the APC inhibitor, avoiding dangerous side effects that plague many anticancer drugs. The APC complex provides "a whole new set of targets which don't function at all in non-dividing cells," says Kirschner.
For successful cell division -- when the cytoplasmic and genetic contents of a cell are faithfully reproduced in the daughter progeny -- two cycles must be synchronized. The DNA is replicated in one cycle, and the chromosomes divide during mitosis -- the second cycle.
The APC is one of the mitotic ringleaders. "It is absolutely required for cell proliferation," says Yu. The protein complex drives a dividing cell from the metaphase stage of mitosis into anaphase--from the point in which the chromosomes find their partner and gather in pairs in the center of the cell, to the point in which each member of the chromosomal pair separates and migrates to the distant cellular poles. A new cell membrane forms between the chromosomal clumps, and mitosis concludes with the formation of two identical daughter cells, each containing an intact copy of the parent cell's genetic information.
An essential step in the development of any new drug is an accurate detection system that will report whether the compound being tested is having the desired effect on the target cell. If APC inhibition is detected following addition of a certain compound the chemical that sounded the alarm can be carefully investigated for its clinical suitability. The Kirschner group has filed a patent for the biochemical method that they devised for analyzing APC activity. The assay is amenable to automation, making it an attractive way to quickly screen many different chemical compounds.
"The intention is to use [the assay] to screen for small molecule inhibitors which might be very useful in anticancer and antiproliferation drugs," says Kirschner.
The study was funded by two grants from the National Institutes of Health.