A long-standing mystery about how cells resist the powerful effects of cancer-causing genes has been solved by researchers studying a genetic check-and-balance system that prevents cells in the body from multiplying chaotically.

Drugs that activate this system, says Charles J. Sherr, an HHMI investigator at St. Jude Children's Research Hospital in Memphis, Tennessee, could increase the effectiveness of conventional anti-cancer therapy.

Cells are equipped with several systems for controlling their multiplication, but when these cease to work properly, uncontrolled cell growth can lead to tumor formation. Sherr and St. Jude colleague Martine F. Roussel have been studying how some of these systems work at the molecular level.

In 1995, the HHMI team discovered an unusual example of such a "checkpoint" whose key component is a protein they named ARF. Now they have learned that this protein "monitors the system carefully and works like a fuse or circuit breaker," Sherr says. "The gene for ARF is not activated until signals that stimulate cell growth exceed a critical threshold. It's as if too much current runs through the circuit and the breaker trips."

Although it is generally thought that one gene encodes one protein, the gene encoding the ARF protein initially escaped attention because it lies embedded within another gene called INK4a. Sherr's group realized that, like the protein specified by the INK4a gene, ARF also inhibits cell growth. The intimate physical relationship between two overlapping genes that ordinarily restrain cell multiplication explains why the INK4a-ARF gene pair is missing in many human cancers. Without the growth inhibitory effects of this gene pair, cells are more likely to grow uncontrollably.

Now, the investigators are refining their understanding of how ARF works. ARF's major role is to monitor various kinds of
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
7-Aug-1998