Loosen leash on cancer protein 'watchdog,' researchers say

Scientists may have found a way to keep a protein "watchdog" on high alert to stop hereditary cancers from overrunning our bodies - if they can keep it on a leash of just the right length.

In a collaborative effort, a team of scientists including Purdue University's Susan M. Mendrysa has found that one of the proteins found naturally in cells has the ability to halt the progression of intestinal tumors that arise from genetic predisposition. When the activity of this protein, known only by the technical name of p53, was artificially increased in the cells of laboratory mice, those known to have a hereditary predisposition for developing cancer showed a marked decrease in tumor development when compared with mice that had normal p53 activity.

The study also indicated that the treated mice did not suffer from the side effect the research team most feared: premature aging, which has been linked to overproduction of p53 in other studies. The discovery could assist in future human cancer treatments.

"It's a question of balance," said Mendrysa (pronounced men-DRISS-ah), who is an assistant professor of basic medical sciences in Purdue's College of Veterinary Medicine and co-lead author of the work. "The p53 protein has been long known as an effective weapon against cancers, but we know from previous research that we can't just let it run rampant through the body without some very unpleasant side effects. But if we can give it just enough slack in its leash, it could help some patients from cancer-prone families from ever developing the disease."

The team's research appears in the Jan. 1 issue of the scientific journal Genes and Development. Members of the group include the University of Wisconsin - Madison's Kathleen A. O'Leary (co-lead author), Matthew K. McElwee and Jennifer Michalowski; the Fred Hutchinson Cancer Research Center's Robert N. Eisenman; and the National Cancer Institute's Mary Ellen Perry and Douglas A. Powell. When the group came together, Mendrysa said, they were primarily concerned with how they might stop their prospective protein watchdog from doing more harm than good.

"Research is turning up lots of possible inroads for combating disease these days, and other research teams had found that p53 was a good prospect for fighting cancer," she said. "With too little p53 protein, people and mice are more likely to develop cancer. But it's not a panacea. Embryonic mice with too much p53 in their systems don't survive gestation. Moreover, recent reports have suggested that high levels of p53 may accelerate aging. Having the wrong amount of p53 protein, therefore, leaves you with two potentially unappealing choices: Do you want to die early of cancer or die early from wearing your body out?"

The scientists theorized that the solution could lie with another protein the body produces naturally to keep p53 in check. This other protein, called Mdm2, keeps p53 inactive until it is needed, acting like a leash on a watchdog.

"p53 seems to be an important stress response gene that fights cancer when it works," Mendrysa said. "So we decided to see what we could do to increase p53's activity without completely cutting its Mdm2 leash."

The scientists spent three years creating a strain of genetically modified mouse that only produced about 20 percent of the normal amount of Mdm2 protein, which is far less than they would have produced under ordinary conditions. The mice were created to answer a twofold question: Could increasing their levels of p53 delay or prevent tumor formation in living creatures, and would there be any negative consequences to the increase?

"We were primarily interested in the second part of the question when we began," Mendrysa said. "These mice had a family trait that typically made them develop cancerous lesions in their intestines, but our main goal was to see whether p53 sped up the aging process. Fortunately, we got more kinds of good news than we initially expected."

Mice with such a predisposition generally developed about 50 intestinal lesions within six months of birth, but mice modified for the study had only developed three or fewer within that time frame. Moreover, there was no sign that the mice had aged any faster than normal.

"We checked for the sort of characteristics that the elderly of many mammal species typically show - thinner skin, lower bone density, spinal hunching and the like," Mendrysa said. "We couldn't find any differences between them and normal mice. And their cancer rates were dramatically lower than expected, which turned out to be the more significant finding of the study."

Mendrysa said the results were an enlightening fundamental discovery about suppressing hereditary intestinal cancers. But she also said the work raised a number of questions that would need to be answered before the research could translate into human therapy.

"These mice were genetically modified at conception to produce higher p53 levels, which is quite a different treatment than just giving normal mice a pill," Mendrysa said. "Also, mice in our study are not subject to the same stresses as, for example, a person working on Wall Street. It remains to be seen whether higher p53, in conjunction with other factors such as stress, could still lead to negative consequences such as aging. We'll have to do a lot more work before this becomes a routine part of medicine's anticancer toolkit.

"Essentially, this study validates Mdm2 as a potentially powerful chemopreventative for some kinds of hereditary cancer, and, if used properly, it might perform well without elevating the risks of aging that other groups have found. The benefits seem to outweigh the risks.

"We'd like to expand the research and look into how Mdm2 and p53 affect other cancer predispositions. If we can find the right length for the leash, someday we may be able to find a way to specify it without resorting to genetic modification. Then we might have a way to keep the watchdog on high alert."

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This research was supported in part by the National Institutes of Health.

Mendrysa is affiliated with the Purdue Cancer Center. One of just seven National Cancer Institute-designated basic-research facilities in the United States, the center attempts to help cancer patients by identifying new molecular targets and designing future agents and drugs for effectively detecting and treating cancer. The center is part of the university's Oncological Sciences Center in Discovery Park.

Writer: Chad Boutin, 765-494-2081, cboutin@purdue.edu

Source: Susan M. Mendrysa, 765-494-8622, mendrysa@purdue.edu

ABSTRACT
Tumor Suppression and Normal Aging in Mice with Constitutively High p53 Activity

Susan M. Mendrysa, Kathleen A. O'Leary, Matthew K. McElwee, Jennifer Michalowski, Robert N. Eisenman, Douglas A. Powell, and Mary Ellen Perry

The p53 inhibitor Mdm2 is a target for potential cancer therapies, however, increased p53 function can be lethal. To directly address whether reduced Mdm2 function can inhibit tumorigenesis without causing detrimental side effects, we exploited a hypomorphic murine allele of mdm2 to compare the effects of decreased levels of Mdm2 and hence increased p53 activity on tumorigenesis and life span in mice. Here we report that mice with decreased levels of Mdm2 are resistant to tumor formation yet do not age prematurely, supporting the notion that Mdm2 is a promising target for cancer therapeutics.


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