Discovered in 1979, p53 causes damaged cells to self-destruct in a process called apoptosis. Mutations in the gene that produces the protein are present in the majority of human cancers. In some malignancies, p53 is deactivated by excessive amounts of its inhibitor protein, Mdm2.

Despite its ability to suppress tumors, p53 can be dangerous, explained Mary Ellen Perry, adjunct scientist in the Laboratory of Protein Dynamics and Signaling at the National Cancer Institute. "You don’t want too much p53," she said. "It has been shown to kill mice if it’s unregulated."

Perry studies the regulation of the p53 tumor suppressor by the Mdm2 protein. In mouse-based experiments, she analyzed whether cell death would occur in a variety of tissues in which Mdm2 was inhibited. Unexpectedly, she found that although p53 activity was heightened in all of the tissues, cell death increased only in a subset–the thymus, spleen, and small intestines–but not in the liver, testes, and colon. These findings indicate that Mdm2 levels could be manipulated to treat some cancers.

"One of the biggest implications is that, because we showed that mice with a range of low levels of Mdm2 have grown to be healthy young adults, you could manipulate levels of Mdm2 in humans," Perry says. One could, for instance, take a drug that inhibits Mdm2, thus activating p53, and not suffer severely toxic side effects, she added. Theoretically, such treatment could be most effective in cancers of the thymus, spleen, and small intestines.

Findings were also unveiled by Gerard Evan, The Gerson and Barbara Bass Bakar Distinguished Professor of Cancer Research at the University of California at San Francisco.

Using lymphoma-prone mice in which p53 can be blocked or restored at will, Evan irradiated two groups. In one, he allowed the tumor suppressor function during irradiation and for two weeks after. In another group, he blocked the tumor suppressor until two weeks after irradiation. To the researcher’s surprise, cancer prevention was greater for the second group than for the first.

The first group suffered radiation-induced illness, since p53 reacted to cells’ DNA damage by causing cell death. When, two weeks later, the protein was blocked, the nascent lymphoma gained a foothold. But the second group did not fall ill from radiation, because their p53 couldn’t act. When it was restored, p53 caused cell death in all DNA-damaged cells which, by that time, were primarily those becoming malignant.

Cancer patients, says Evan, could conceivably take a p53-blocking drug while they are treated with chemotherapy or radiation. The patient wouldn’t become ill from treatment, because the tumor suppressor could not attack treatment-damaged but otherwise healthy cells. Vulnerable cancer cells, however, would die in droves from treatment.

Reporting unexpected findings from another hot area of cancer research, Zhi-Min Yuan, James Stevens Simmons Associate Professor of Radiobiology in the Department of Genetics and Complex Diseases, discussed an epithelial-related mechanism through which breast cancer may spread. One of the body’s major tissues, the epithelium is involved in 90 percent of human cancers.

Yuan used an unusual laboratory culture in which several breast-related cell types interact; typical cultures contain only one tissue type. With this model, Yuan discovered that stromal cells, which are furthest down in the epithelium, can serve as gatekeepers of cancer development and spread. When exposed to even low doses of radiation, this connective tissue aged prematurely, reaching a stage called senescence. In this state, stromal tissues caused malignant cells to form and spread.

--EM