May 25, 1999 CHAPEL HILL, N.C. - Scientists at the University of North Carolina at Chapel Hill have discovered the molecular role in cancer development of a mutated tumor suppressor gene known as ARF.
The new findings help clarify why ARF is the second most frequently mutated gene in human cancers, appearing in 40 percent of malignancies, second only to the mutated tumor suppressor gene, p53.
According to a report in the journal Molecular Cell, published May 20, ARF normally prevents cellular transformation by preventing degradation of the p53 protein. It allows p53 to accumulate in the cell's nucleus where it functions to stop tumor cell growth.
"We previously reported our discovery that the ARF protein functions to suppress tumor growth by biochemically binding to another protein called MDM2," says Dr. Yue Xiong, assistant professor of biochemistry and biophysics at the UNC-CH School of Medicine. "Under normal conditions, MDM2 binds with p53 and takes it to the cellular cytoplasm for degradation. ARF will stop this process, accumulating p53 in the nucleus."
In the new study, Xiong and Dr.Yanping Zhang, a postdoctoral researcher in his laboratory at the UNC Lineberger Comprehensive Cancer Center, for the first time have described how a normally-functioning ARF does that. Essentially, it binds with MDM2 and p53 to form a structure called a nuclear body. This structure prevents MDM2 and p53 from leaving the nucleus and entering the cytoplasm, where the proteins would otherwise be degraded, broken down.
"When these proteins all come together, p53 cannot go from the nucleus to the cytoplasm. So ARF blocks p53 nuclear export," Xiong says.
The researchers also focused on what happens when ARF becomes mutated. They demonstrated for the first time how the ability of a mutated ARF to fulfill its tumor-suppressing role is impaired - a demonstration based on three discoveries.
First, Zhang and Xiong discovered that ARF is normally located in the cell's nucleolis, a small rounded mass within the cell's nucleus. Second, they determined the DNA sequence in ARF (located in an area of the gene called Exon 2) that is responsible for "localizing" or getting this protein directly to the nucleolis.
This finding led them to link ARF's Exon 2 with cancer, "because many ARF mutations associated with human cancer are clustered in this area and are predicted to disrupt ARF's normal localization," Xiong explains.
"So we tested whether mutations derived from cancer patients would mislocalize ARF and impair its ability to block p53 export and degradation. The answer is yes," Xiong states. "With ARF mutated and mislocalized, oncogenes go unchecked and cells proliferate abnormally, initiating oncogenesis."
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