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Study reveals molecular key to tumor suppressor activity

CHAPEL HILL - New research published Friday June 8 in the journal Science explains for the first time how an important tumor suppressor gene, p53, is activated in response to DNA damage to keep cancer tumors in check.

About half of all human cancers are defective in p53 function. Thus, the new findings may have implications for the development of drugs aimed at boosting p53 activity in cancer patients. The gene normally monitors biochemical signals indicating the occurrence of DNA damage or mutations associated with tumor development. When such signals occur, the p53 protein accumulates in the cell nucleus where it can either program the cell to self-destruct or arrest its cycle of growth.

Led by Yue Xiong, PhD, scientists at the University of North Carolina's Lineberger Comprehensive Cancer Center report having discovered an amino acid sequence within p53 that is responsible for transporting the protein from the cell nucleus to the cytoplasm, where it would get degraded, broken down. Moreover, they discovered how this transport is blocked when DNA damage occurs. "P53 is not needed in normal cell growth under conditions of no DNA damage. Otherwise, the cell won't be able to grow," Xiong said. "So the cell handles that by exporting p53 from the nucleus to the cytoplasm for degradation."

According to Xiong, associate professor of biochemistry and biophysics at UNC-CH School of Medicine and a member of the cancer center, DNA damage triggers multiple cell signaling pathways aimed at insuring that p53 accumulates in the nucleus by adding a phosphate to the protein. Previous research has shown that this phosphorylation process is somehow associated with p53 activation.

The new study elucidates the mechanism underlying P53 activation induced by DNA damage. "We found that the addition of the phosphate inhibits the export of p53 to the cytoplasm. We found a small sequence or small peptide in p53 that's required for p53 to be exported out. And we al
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Contact: Leslie Lang
llang@med.unc.edu
919-843-9687
University of North Carolina School of Medicine
7-Jun-2001


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