Friday, December 14, 2007

P53, a versatile gene

P53 is well-known for its role in regulating the cell cycle so as to suspend the cycle or even lead to cell death via apoptosis in case damage to a cell's DNA is detected. This function is especially important in forestalling cancer.

And as we noted here, p53 is also involved with skin tanning.

But that's not all p53 is good for. It also plays a role in fertility, which has recently been reported by one of the co-discoverers (Arnold Levine) of p53:

Cancer Fighter May Be Fertility Helper
A protein known primarily for its role in fighting cancer also helps embryos implant in the womb, according to a study in mice. The find may explain why some women have difficulty becoming pregnant.

More information: here, here

But the list of p53's goodness doesn't stop there. It also slows aging, apart from deterring cancer, but via the same mechanism:

Anti-cancer gene p53 doubles up as anti-ageing agent
The latest research suggests that one of the genes that protects us from cancer may also help delay the ageing process.

A new study has found that a particular gene, p53 which has been previously linked to premature ageing, along with one of its cellular regulators, called Arf, may boost the body's antioxidant activity to keep cells younger longer and thereby slow down the aging process.

The regulatory chemical Arf, lets p53 know that a particular cell is in trouble and marked for elimination.

More information: here, here, here, here

But, surprisingly, at least in fruit flies, reducing p53 activity may also increase lifespan, and apparently in the same way that calorie restriction does:

Key To Longer Life (in Flies) Lies In Just 14 Brain Cells
Two years ago, Brown University researchers discovered something startling: Decrease the activity of the cancer-suppressing protein p53 and you can make fruit flies live significantly longer.

Now the same team reports an intriguing follow-up finding. The p53 protein, they found, may work its lifespan-extending magic in only 14 insulin-producing cells in the fly brain.

How was this connected with calorie restriction? Simply by noting that calorie restriction in fruit flies didn't increase longevity when p53 activity was suppressed in only 14 insulin-producing cells of the flies' brains:
Studies have shown that low-calorie diets can significantly increase the lifespan of flies, worms, mice and rats. The phenomenon is of intense interest to researchers who study aging. They want to know if caloric restriction works in people and if drugs could be made to mimic its effects.

So researchers restricted the diets of the flies and ran the same experiments. The calorie-restricted flies didn't live any longer when p53 was reduced in the insulin-producing cells. This evidence supports the notion that p53 reduction is one of the direct effects of caloric restriction.

Even more intriguing, Helfand said, is the fact that the 14 insulin-producing cells that seem to be critical for lifespan extension are the equivalent of beta cells in the human pancreas. Beta cells make and release insulin, the hormone that controls the level of glucose in the blood. The research team found that when p53 activity drops, so does insulin-responsive activity in the fat body, the major metabolic organ in the fruit fly.

The involvement of insulin in this effect is especially interesting, as insulin signaling has also been found to be involved in the mechanism by which sirtuin proteins extend longevity in nematodes and fruit flies (and perhaps other organisms).

One wonders just how p53 came to play such a prominent role in cellular processes. Some researchers think they have found the answer – endogenous retroviruses that have actually proven beneficial to the host genome:

Ancient Retroviruses Spurred Evolution Of Gene Regulatory Networks In Humans And Other Primates
Scientists have long wondered how a master regulator such as p53 gained the ability to turn on and off a broad range of other genes related to cell division, DNA repair, and programmed cell death. How did p53 build its complex and powerful empire, so to speak?

Using the tools of computational genomics, the UCSC team gathered compelling evidence that retroviruses helped out. ERVs jumped into new positions throughout the human genome and spread numerous copies of repetitive DNA sequences that allowed p53 to regulate many other genes, the team contends.

"This would have provided a mechanism to quickly establish a gene regulatory network in a very short evolutionary time frame," said Ting Wang, a post-doctoral researcher at UCSC and lead author of the paper.

It's hard to avoid a suspicion that there's a lot to the story of p53 left to be discovered.

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