Sci. Aging Knowl. Environ., 20 November 2002
Having It All After All
p53 surplus staves off cancer but doesn't speed aging
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2002/46/nf13
An ever-present police force can make a law-abiding community feel restless rather than safe. But when a riot ensues, some extra muscle preserves the peace. A cellular guardian behaves similarly, according to new research. Previous studies have suggested that bumping up amounts of the antitumor protein p53 accelerates aging in otherwise healthy mice, but it protects them against cancer. Now scientists reveal that bolstering the p53 force--but only when cellular mayhem occurs--can thwart cancer, apparently without sparking other problems that speed an animal's demise. "It's exciting," says cancer biologist Lawrence Donehower of Baylor College of Medicine in Houston, Texas. "It suggests that you can have it both ways: You can reduce cancer without getting premature aging." Additional work is needed to verify that the mice don't age more rapidly than normal and that p53--and not another gene--underlies the effect.
When cells suffer DNA damage or overproduce growth-spurring proteins, the p53 protein jumps into action. It temporarily stops cells from dividing so that they can repair themselves; if the genetic and reproductive turmoil is severe, it initiates cell suicide. p53 is apparently a crucial barrier to cancer development: Half of human tumors carry mutations that cripple p53, and many chemotherapy drugs work by boosting p53 function.
Although p53 keeps bad cells from taking over, too much of the protein might cause trouble. In addition to stalling or killing cultured cells, the protein can send them into a zombielike state known as senescence, in which they permanently stop dividing but don't die. Although the relevance of senescence in whole animals remains unclear, senescent cells might speed aging (see "More Than a Sum of Our Cells"). For example, senescence could deplete stem cell stores, making it difficult to replenish haggard tissues. Because cells need p53 to senesce, overactive p53 might promote aging even as it reduces cancer.
Recent studies tested this idea. In January, Donehower and colleagues reported that they had created mice that carry one normal copy of the p53 gene and one copy in which the first half is lopped off. The mutant gene generates a short form of the p53 protein that apparently slows the breakdown of the normal version and thus elevates its activity. The manipulated mice fight off cancer more fiercely than do their normal counterparts, but at a price: They die young and show early signs of aging, such as hair loss and curved spines (see Campisi Perspective). Although the effect was dramatic, questions arose about whether the changes stemmed from p53 or from one of the many other genes deleted in the animals.
A second study bolstered the idea that p53 contributes to aging. Mice that are missing a smaller portion of p53, and no adjacent genes, also age rapidly and remain untouched by cancer, according to a preliminary report by neurogeneticist Heidi Scrable and colleagues at the University of Virginia in Charlottesville (see "Tumor-Free, But Not in the Clear").
Some mice can apparently hit the p53 jackpot, however. In new work, molecular biologist Manuel Serrano and colleagues at the Spanish National Center for Biotechnology in Madrid aimed to create cancer-resistant mice by augmenting normal p53. The team isolated a large chunk of mouse DNA that contains the p53 gene and reintroduced the section so that the animals carried three copies of the p53 gene. By using such a big piece of DNA, the team hoped to include elements that turn the gene on and off appropriately.
The researchers first showed that the third p53 gene responded to DNA-damaging agents as the resident genes do: Cultured cells that contained one original p53 gene plus the introduced one responded to damage and senesced as do cells with two normal p53 genes. And cells with activated cancer proteins didn't grow out of control when they carried a copy of the introduced gene, but they displayed signs of tumor formation when the researchers removed it as well as the other copy of p53. "They showed pretty convincingly that it functions the same way normal p53 does," says Scrable.
The researchers then turned to the mice with three copies of the p53 gene. Radiation activates p53, which in turn cranks up production of other proteins, including one called p21. The extra copy of p53 ignited an unusually large burst of p21 after irradiation, suggesting that the mice have a heightened p53 response. When the scientists treated mice with carcinogenic chemicals to promote tumor formation, nearly all of the normal animals developed tumors, whereas fewer than half of those with three copies of p53 got cancer. Together, the results suggest that the extra copy of p53 enhances resistance to cancer-causing agents.
To determine whether additional p53 alters mouse life-span, the team counted the number of animals that remained alive after 2 years. Mice that carried one extra copy of the p53 gene lived as long as their normal siblings did: 70% of the rodents in all three groups survived to age 2. In addition, they showed no signs of premature aging, as measured by four indicators: speed of hair growth, extent of spine curvature, bone density, and skin thickness.
The new results suggest that "there's a dose of p53 that acts as a tumor suppressor but doesn't come with a cost," says oncologist Ned Sharpless of the University of North Carolina, Chapel Hill. At first the observations appear to conflict with those of Donehower and Scrable. But because the teams boosted p53 in different ways, the results can be reconciled. "I don't really think they're in contradiction," says Sharpless. Donehower's mice likely churn out some p53 all the time, he says, whereas Serrano's make p53 only when necessary because they retain the gene's control regions. Donehower agrees: "There may be more cells undergoing senescence in our mice than in his," because DNA sequences that restrict p53 production are absent. What's more, the size of the p53 protein probably matters. Scrable says that cells normally produce small amounts of her short version. Because her gene and Donehower's gene make only cropped p53, they could be upsetting the ratio of small to large protein. That change could be crucial for premature aging, she speculates. By introducing a full-length gene, Serrano's team "maintains the normal ratio of the proteins," she says.
The new study doesn't lock up the idea that added cancer-fighting power comes with no strings attached, however. The work didn't directly measure p53 protein quantities and assessed mortality in a small population at only a single age, says molecular biologist Judith Campisi of Lawrence Berkeley National Laboratory in California. In addition, Serrano introduced a piece of DNA that carries several genes, so scientists can't formally attribute the physiological magic to the anticancer protein. Still, "there's something to those mice," Campisi says. She adds that a better understanding of p53's role in aging and cancer will allow scientists to "take apart the molecule to figure out a way to make it better at what we want [it to do] and worse at what we don't." And that analysis could lead to ways of preventing cancer without instigating other unrest.
November 20, 2002
R. John Davenport is an associate editor of SAGE KE based in Santa Cruz, California. He wants it all, but for now he'll settle for a new surfboard.
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Citation: R. J. Davenport, Having It All After All. Science's SAGE KE (20 November 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/46/nf13
Science of Aging Knowledge Environment. ISSN 1539-6150