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November 25, 2005

New clues to the dark side of the p53 protein - a key anti-tumor guardian

Topics: Medicine

p53.gifFew of us have stayed awake nights wondering about a possible dark side to the p53 tumor suppressor gene, a tumor suppressor gene with activity that stops the formation of tumors. p53 regulates the cell cycle, plays a key role in ensuring that damaged cells are destroyed by apoptosis (programmed cell death), and is the most commonly mutated gene associated with cancer. And that's why you should care about both it's benefits and it's negative side effects.

Past work has shown that in animal models, hyperactivation of the p53 protein is beneficial in terms of providing protection against tumor formation, while at the same time it has been shown to have several significant negative effects such as a shortening of lifespan, accompanied by indications of accelerated aging (interestingly, research into the aging effects of p53 may have been stimulated by research into a relationship between p53 signaling pathways and progeria). Until recently, the mechanisms by which activation of p53 expression might contribute to aging and lifespan haven't been well studied.

However, researchers studying p53 function in fruit flies, and reporting in Current Biology, Vol. 15, 2063-2068, November 22, 2005, have shown 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 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.

So will cell-targeted modulation of p53 signaling activity become another tool in our fight against cancer? An intriquing possibility perhaps, but a long way off from clinical testing. In the meanwhile, everytime we discover another mechanism for gene expression and/or alteration thereof, we're another step closer toward learning how to more effectively "individualize" cancer treatment.

And that is the direction that will result in more patients suffering less, and living longer. ( It has long been recognized that every person with cancer is markedly different from other patients.)

The next revolution in radiology: personalized cancer treatment
Cancers In The Cross-Hairs - "Replacing many early treatments that destroyed healthy cells along with cancerous ones, innovative cancer medicine is heading toward individualized cancer care, delivering highly selective, targeted therapies."

Posted by Richard at November 25, 2005 2:31 PM

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