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Fox Chase Cancer Center researchers make significant discovery about function of p53

03.02.2003


Cancer researchers have known that the tumor-suppressor gene p53 is critical in preventing cells from dividing inappropriately and becoming tumors. But now, researchers at Fox Chase Cancer Center have established that the ability of the p53 gene to perform its job depends on the type of p53 within each cell. This and another new finding about p53, published in Nature Genetics (Feb. 3, 2003 online version, March 2003 print version), have implications for tailoring chemotherapy, designing new cancer treatments, and understanding how to treat cancer in certain populations.



“The existence of two variants, or polymorphisms, of p53 isn’t new, but we’ve discovered that the variant type in each cell can influence its tumor-suppressor ability,” explains senior author Maureen Murphy, Ph.D., a molecular biologist in the pharmacology department of Fox Chase Cancer Center, Philadelphia, Pa.

When functioning properly, p53 polices cells for problems such as errant cellular growth, the hallmark of human cancer. If such harmful factors are present, p53 triggers the process of programmed cell death (known as apoptosis)-in effect, causing the “bad” cells to self-destruct. Alterations, or mutations, in this gene have been found in more than 60 percent of human cancers.


Murphy and her colleagues have known about the two p53 variants, but how the differences affect p53’s ability to suppress tumor development was not previously understood until now.

“People have one form or another of p53,” says Murphy. “The p53 variant containing the amino acid called arginine is better at killing out-of-control cells. The other p53 variant with the amino acid proline is less capable of stopping errant cells. When we asked if the two forms might function differently, the answer was a resounding yes.

“In terms of treating cancer, patients could potentially be typed for the kind of p53 they have, some day allowing physicians to tailor their therapy. If a patient has the arginine p53, which kills cells better, relatively less drugs might be needed for that person’s body to kill tumor cells. If another patient has the proline form, which is less active, relatively more drugs may be needed to fight the tumor.”

Although p53 variants have not received much attention from the biomedical community until now, epidemiologists have known that the proline form has an enhanced frequency in African Americans. This variant, which is less likely to set off programmed cell death, is more frequent in populations who live closer to the equator and have darker skin color. As a result, “p53 variants seem to differ according to ethnicity, and that might have implications for cancer treatment in different populations,” says Murphy.

The published research also redefines the function of p53. The p53 protein normally resides in the nucleus, and the way scientists have hypothesized its control of cell death is that it “turns on” the proteins that tell a cell to die or “turns off” the proteins that tell a cell to live. When the researchers couldn’t find a difference between the two forms with regard to activity inside the nucleus, they turned their attention to a little-studied area of p53 activity outside the nucleus—in the mitochondria, the energy storehouse of the cell.

“We looked at this and found a dramatic difference between the two forms,” recalls Murphy. They found that the arginine form, which is more efficient at killing cells, travels out of the nucleus better and into the mitochondria, where p53 functions to kill the cell.

Murphy adds, “Not only did we find a common polymorphism that influences tumor suppression, we also found that this seemingly obscure activity is at the center of how this protein kills cells.”

By bringing the mitochondrial pathway of cell death to the forefront of research, the investigators suggest that drugs could be designed to put p53 directly into the mitochondria or enable the cell to put it there. In the paper, they begin to test this hypothesis. They showed that if a drug is administered that prevents p53 from going to the mitochondria, then it inhibits the ability of p53 to kill a cell. Future efforts will focus on identifying drugs that enhance the ability of p53 to go to the mitochondria.


Fox Chase Cancer Center, one of the nation’s first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at www.fccc.edu or call 1-888-FOX CHASE.

"The codon 72polymorphic variants of p53 demonstrate significant differences in apoptotic potential" Nature Genetics (Feb. 3, 2003 online version, March 2003 print version). http://press.nature.com.

This research was conducted equally by Patrick Dumont, a postdoctoral fellow in the Murphy lab, and Julie Leu, a postdoc in the lab of Donna L. George, from the Department of Genetics at the University of Pennsylvania School of Medicine. Anthony C. Della Pietra III from the Murphy lab also participated in the research.


Karen Mallet | EurekAlert!
Further information:
http://www.fccc.edu/
http://press.nature.com

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