UNC-CH Researchers Discover Key Cancer Control Mechanism

March 22, 1998

UNC-CH News Services

CHAPEL HILL -- A gene called ARF attaches to and disables a protein known as MDM2 and in the process helps protect the body against cancer, University of North Carolina at Chapel Hill School of Medicine researchers have discovered.

The mechanism appears to be one of the most potent natural ways of fighting tumor development, the scientists say. After more research, it might be manipulated to treat cancer more successfully or detect it earlier.

"While this work is not a cure for cancer, it is very important for several reasons," said Dr. Yue Xiong, assistant professor of biochemistry at the UNC Lineberger Comprehensive Cancer Center. "First, it provides a mechanism by which ARF suppresses tumor growth. It also may explain why a certain genetic locus, or site on a chromosome, is frequently missing in human cancer." A report on the discovery appears in the current (March 20) issue of Cell, a scientific journal. Besides Xiong (pronounced "Jong"), authors are Dr. Yanping Zhang, a postdoctoral fellow at the Lineberger center, and Dr. Wendell G. Yarbrough, assistant professor of surgery.

In human cancers, a gene known as P53 is mutated in about 50 percent of cases, Xiong said. The ARF gene is missing in about 40 percent.

"When activated, both these genes suppress tumors. When they are absent or damaged, we have a much greater chance of developing tumors," he said.

Soon after the body detects damage to DNA that might lead to cancer, normally low levels of P53 skyrocket and halt cell proliferation similar to how a fire extinguisher smothers a blaze, Xiong said. Healthy cells keep P53 in check when it is not needed by degrading it with the MDM2 protein.

"When DNA is damaged, MDM2 must be decreased to allow the protective P53 to increase," he said. "If cells get too much MDM2, that will reduce P53 even in case of damage that might cause cancer."

MDM2, which researchers call a proto-oncogene, is amplified, for example, in almost half of sarcomas, a cancer of bones, blood vessels and other tissues. A proto-oncogene is a gene all humans carry that results in cancer if it is altered in certain ways.

In complicated experiments involving both yeast and human genes, the UNC-CH researchers found the ARF gene physically binds to MDM2 and destroys it.

"When DNA is damaged, ARF degrades MDM2 to allow P53 to accumulate," Xiong said. "However, when ARF is deleted, which happens in about 40 percent of human cancers, it can't stop the MDM2 from degrading P53. Then there's not enough P53 to fight tumors."

On a one-to-10 scale, Yarbrough said he thought the new finding rated a 10. He is interested in the research because he performs surgery on head- and neck-cancer patients.

"The fact that one gene makes two products that control two major tumor suppressers I think has some potentially huge implications for cancer development and possibly future treatments," the surgeon said. "It looks like this is going to evolve into a pretty big deal."
Note: Yarbrough can be reached by calling the hospital paging operator at (919) 966-4131 (work) or at 932-6160 (home). Zhang and Xiong can be reached at (919) 962-2142. Xiong's home # is 929-6658.

Contact: David Williamson, (919) 962-8596

University of North Carolina at Chapel Hill

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