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Study Reveals Molecular Key To Tumor Suppressor Activity

Date:
June 11, 2001
Source:
University Of North Carolina School Of Medicine
Summary:
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.

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 also determined that phosphorylation occurs in that area," Xiong said. "We discovered this in normal cells, but we can also take tumor cells in which p53 is not working and insert functioning p53 into the nucleus and it will remain there."

In addition to further understanding a cellular control mechanism of p53, Xiong's findings have other implications.

"Protein transport is a major regulator of cellular function. This represents one of the first examples where a nuclear exporting signal can be regulated by phosphorylation," he said.

"In half of all tumor cells p53 is not working, sometimes because a kinase gene responsible for p53 phosphorylation is mutated. When that gene is broken, DNA damage cannot be repaired because P53 is continually exported to the cytoplasm and getting degraded there. So one could imagine if we were to develop a compound to block p53 export, we might be able to restore p53 function in tumor cells with mutated kinase genes. We could give the compound to patients to wake up the p53 or prevent its degradation."

Thus the new study explains the molecular site of an all-important effect on p53 of phosphorylation. "By continuing this line of research we hope to understand exactly how the phosphate signal shuts the door on p53 export," Xiong said. "That knowledge can be used to develop a targeted treatment for malignant tumors."

A major contributor to this study was Yanping Zhang, PhD, a former postdoctoral research fellow in Xiong's laboratory, now at M.D. Anderson Cancer Center in Houston, Texas. This study was supported by a grant from the National Institutes of Health.


Story Source:

The above story is based on materials provided by University Of North Carolina School Of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

University Of North Carolina School Of Medicine. "Study Reveals Molecular Key To Tumor Suppressor Activity." ScienceDaily. ScienceDaily, 11 June 2001. <www.sciencedaily.com/releases/2001/06/010608081400.htm>.
University Of North Carolina School Of Medicine. (2001, June 11). Study Reveals Molecular Key To Tumor Suppressor Activity. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2001/06/010608081400.htm
University Of North Carolina School Of Medicine. "Study Reveals Molecular Key To Tumor Suppressor Activity." ScienceDaily. www.sciencedaily.com/releases/2001/06/010608081400.htm (accessed September 1, 2014).

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