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New clues to the dark side of a key anti-tumor guardian

Cell Press

The p53 protein is known to be a critical player in our body's natural defense against cancer--it is absent in many types of tumor cells--but it also represents an intriguing paradox when it comes to the broader roles this protein plays in our well being. Past work has shown that in animal models, hyperactivation of the p53 protein is beneficial in terms of bestowing extra protection against tumor formation, but at the same time it has a significant negative effect: a shortening of lifespan, accompanied by hallmarks of accelerated aging, including osteoporosis, decreased stress resistance, and organ atrophy. Although researchers over recent years have established a foothold in understanding how p53 protects against cancer, the mechanisms by which it might contribute to aging and lifespan are not well studied. In work reported this week, researchers studying p53 function in fruit flies show new evidence that despite the protective role of p53 as a guardian against tumor formation, normal levels of p53 activity--at least in some cell types--may indeed contribute to aging and decreased lifespan.

The work is reported by Stephen Helfand and colleagues at Brown Universtiy, University of Connecticut Health Center, and University of Texas Southwest Medical Center.

The researchers investigated the role of p53 in aging by observing the effects of disrupting this protein in the neurons of adult fruit flies. They found that expression of a so-called "dominant-negative" version of p53--that is, a disfunctional version of the protein that inhibits the activity of normal p53--extended flies' life span and increased their ability to withstand gene-damaging stress. The authors found that this disruption of p53 did not further increase the lifespan of flies on a calorie-restricted diet, suggesting that decreased p53 activity and calorie restriction may influence lifespan through a common molecular mechanism.

Because neurons are less prone to tumor formation than other cell types, and because disruption of p53 activity in neurons was sufficient to extend lifespan in the fruit fly, the new findings suggest that by attending to p53 activity in different cell types, it may be possible to take therapeutic advantage of p53's tumor-preventing activity while avoiding its unwanted negative effects on lifespan.

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The researchers included Johannes H. Bauer, Peter C. Poon, Heather Glatt-Deeley and Stephen L. Helfand of the University of Connecticut Health Center in Farmington, Connecticut; John M. Abrams of the University of Texas Southwestern Medical Center in Dallas, Texas. This research was supported by grants from the NIA (AG16667, AG24353), the Donaghue Foundation, and the Ellison Medical Foundation to S.L.H.

Bauer et al.: "Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span." Publishing in Current Biology, Vol. 15, 2063-2068, November 22, 2005, DOI 10.1016/j.cub.2005.10.051 www.current-biology.com

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