Tumor-Free, But Not in the Clear
Authors: Davenport R. John 
Published: August 2003

COLD SPRING HARBOR, NEW YORK
--Like a good mother, the p53 protein watches over a cell to protect its DNA. But a deviant partner spurs p53 to sour an organism's future. An altered version of the tumor-blocker accelerates degeneration and makes mice small, apparently by sparking a hormone pathway, according to research presented here 3 October at the Cold Spring Harbor Laboratory's Molecular Genetics of Aging meeting.

p53 halts cancer by preventing damaged cells from dividing or by goading them to commit suicide. Previous work suggested that stabilizing p53 accelerates mouse aging despite making cancer infrequent, although questions remain because the animal carries genetic alterations in addition to the one in p53 (see
Campisi Perspective
).

Part of p53 is missing in a particular strain of mice infected with a leukemia virus. To learn more about the variant, geneticist Heidi Scrable and colleagues at the University of Virginia, Charlottesville, modified mice to carry a gene that produces the shortened version of p53, dubbed p44. Rodents that pump out p44 and p53 developed no tumors but showed signs of premature aging, such as reduced muscle mass and decreased fertility; the animals were also half normal size. p53 molecules work in teams of four; p44 might infiltrate to create mixed groups. Because p44 lacks a region that causes its degradation, the new quartet is probably unusually stable. A drop in the animals' cell number might underlie their size difference: Mothers containing p44 produced embryos that harbored fewer cells than normal, although the cells were regular size. Moreover, cells cultured from p44-carrying embryos proliferated slowly. Scrable speculates that the introduction of p44 prods p53 to slow cell division.

The animals' small size hinted that growth-stimulating pathways might be blocked. But further experiments suggest that p44 and p53 together instead crank up the insulin-like growth factor-1 (IGF-1) pathway, a molecular relay that promotes growth and perhaps aging in mammals (see
Bartke Viewpoint
); a related pathway curbs life-span in flies and nematodes (see

Strauss
Science
Article

).

Compared with controls, cells from the p44-containing animals harbored large amounts of the IGF-1 receptor protein as well as the activated form of Akt, a protein that it stimulates. p53 normally blocks these components of the IGF-1 pathway. Scrable doesn't know why the p44-p53 combination provokes rather than suppresses the pathway, but the effect might stem from the fact that p44 lacks a segment to which regulatory proteins bind and it therefore alters how p53 turns on genes.

The IGF-1 changes match observations in nematodes, says molecular geneticist Cynthia Kenyon of the University of California, San Francisco. "It's really clear that if you turn up IGF-1[-related signaling], worms have a short life-span." What isn't clear is why the animals are small, says Kenyon. Perhaps another altered cellular signal overrides IGF-1's growth-spurring effect, she suggests. The study backs the emerging hypothesis that unchecked p53 causes premature aging, says geneticist Ronald dePinho of Harvard University, and it is the first to suggest that p53 acts early in embryonic development. Further work could reveal how to help p53 raise a happy cellular family.

--R. John Davenport

W. Gluba, A. Sutherland, H. Scrable, Growth deficiency and early aging in p44/p53 mice. Cold Spring Harbor Laboratory, Molecular Genetics of Aging, 2 to 6 October 2002, Cold Spring Harbor, New York.
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