Evolution boosted anti-cancer prowess of a primordial gene

Arf gene became more effective in stemming cell growth when it joined forces with p53

Researchers at St. Jude Children’s Research Hospital have looked back in evolutionary time and identified what may be a gene that was once only moderately effective in slowing down cellular reproduction, until it linked up with a more efficient set of genes to create a powerful anti-cancer response.

The gene, called Arf, was already known to have cancer-suppressing activity. Arf responds to cancer-causing environments by activating the well-known tumor suppressor gene, p53. In turn, p53 activates a battery of other genes to stop cell growth or, in extreme cases, to trigger cell death in response to a variety of harmful conditions, such as DNA damage or activation of oncogenes (cancer-causing genes). In fact, loss of Arf or p53 is a common event in many human cancers.

But the new results suggest that Arf plays a role far older in evolutionary terms than its more familiar job of stimulating p53 to prevent cancer. The St. Jude findings suggest that Arf originally evolved to slow the cell’s metabolism and growth by limiting production of ribosomes. Ribosomes, made up of RNA (de-coded DNA) and proteins, guide the production of all other cellular proteins according to the genetic code. The new work shows that Arf interferes with production of the RNA components of ribosomes in order to exert some control of protein production and cell growth.

“About 80 percent of a cell’s RNA is tied up in ribosomes,” said Charles Sherr, M.D., Ph.D., a member of the Genetics & Tumor Cell Biology Department at St. Jude and a Howard Hughes Medical Institute investigator. “In fact, producing ribosomes is practically what cells do for a living. It’s their major energy-consuming activity. So it makes sense that any limitation on ribosome production would slow cell growth.”

Sherr’s team believes that Arf counteracts excessive growth-promoting stimuli by interfering with ribosome production. But inhibiting ribosomal production isn’t a particularly efficient way to control cell growth. “On the other hand, p53 activates many growth suppressive genes,” Sherr said. “So Arf appears to have become more efficient because, by evolving a way to activate p53, it was able to extend its reach and inhibit many more cellular responses apart from ribosome synthesis.”

Sherr is senior author of a report on these findings published in the February 2003 issue of Molecular Cell. Other authors of the study include Masataka Sugimoto, Mei-Ling Kuo and Martine F. Roussel, all of whom are St. Jude investigators.

The group studied the role of Arf in controlling ribosomal RNA production using a variety of mouse cells. The effects were then examined by inserting Arf genes into harmless viruses used to infect the cells, and by tracking the levels of newly synthesized RNA in the cells under various experimental conditions. The exact mechanism by which Arf interferes with ribosomal RNA synthesis remains unclear and is a subject for future research, according to Sherr.

This work was supported by the Howard Hughes Medical Institute, an NIH Cancer Center Core Grant to St. Jude Children’s Research Hospital and by ALSAC, the fund-raising arm of St. Jude.

About St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children’s Research Hospital. Families without insurance are never asked to pay. For more information, please visit www.stjude.org.