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Little-known little protein packs punch in cancer fight

WASHINGTON — It's a tiny molecule with a nondescript name — "p53" — but it has an awesome responsibility: preventing more than half of all human cancers.

Some scientists call it the "guardian angel," "guardian of the genome," or the "dictator of life and death."

P53 is a protein, a string of 393 chemical units stored in the DNA of most of the body's cells. Normally, p53 works to suppress malignant tumors. When it's missing or mutated, however, it can't carry out its lifesaving mission and lets cancerous cells run amok.

Scientists are developing drugs to repair or restore damaged p53 in mice, but so far none of those drugs are ready to treat human cancers.

Almost 50,000 papers about p53 have been published in scientific journals, but its workings are still not fully understood, and it's little known outside the worlds of biology and medicine.

P53 is "certainly the most studied protein in the whole history of cancer," Magali Olivier, an expert at the World Health Organization's International Agency for Research on Cancer in Lyons, France, wrote in the journal Cancer Gene Therapy this fall.

Arnold Levine, a cancer expert at the Institute for Advanced Study in Princeton, N.J., who discovered p53 almost 30 years ago, said "We have uncovered and explored a process central to life — how a cell responds to stress or perturbation in its environment."

Here's how it works: A normal p53 protein detects a patch of DNA in the nucleus of a cell that has been damaged by accident, a virus, radiation, smoking or other environmental assaults, raising the chance that the cell will turn cancerous. P53 triggers a complex biochemical program that stops the pre-cancerous cell from dividing until it repairs its DNA or commits suicide.

When p53 itself is flawed, however, it allows other cancer-causing genes (known as oncogenes) to hijack the cell's control machinery and set it free to spread wildly — the hallmark of cancer.

"Loss of p53 function in cells leads to uncontrolled proliferation and promotes cancer development," Olivier wrote in a summary of recent p53 research.

The gene that carries the instructions to make p53 is called TP53. Mutations in the gene may be inherited, which is why some cancers run in families.

TP53 is "the most mutated gene in human cancer, and these mutations are correlated with more than 50 percent of all human cancer," said Ronen Marmorstein, an expert on gene regulation at the Wistar Institute in West Philadelphia, Pa.

According to Gerard Evan, a researcher at the University of California's Comprehensive Cancer Center in San Francisco, p53 mutations are also associated with more aggressive cancers, resistance to treatment by radiation and chemotherapy, and decreased patient survival.

Despite the vast amount of research, work is only beginning on cancer therapies based on fixing damaged p53.

Nevertheless, hopes are rising that the immense body of knowledge about p53 will lead to better ways to diagnose, prevent and treat cancer.

"The growing number of p53-targeting strategies raises hope for more efficient cancer therapies in the future," reported Swedish researcher Klas Wiman in the journal Cell Death and Differentiation.

In an experiment in his San Francisco lab, for example, Evan restored damaged p53 in mice suffering from lymphoma.

"The tumors were completely dead within hours." Evan said. "This result is very good news to the many of us who are thinking about trying to restore p53 function in established human cancers."

Unfortunately, restoring p53 may cause accelerated aging, at least in mouse experiments.

"Cancer and senescence may be seen as two alternative fates in aging organisms, the secret of longevity being to find the best possible trade-off between these two options," Olivier reported.

Many questions remain about the workings of p53.

"Complete understanding still remains elusive," Antony Braithwaite, a New Zealand researcher, wrote in Cell Death and Differentiation. "How p53 makes decisions to do one thing or another, or turn on one gene or another, is far from clear."

To accomplish its job, p53 has to scan three billion letters in the human genetic code to decide which genes it's going to activate or repress. "This is a tall order," Braithwaite wrote.


For more information on p53

To see Cancer Gene Therapy's summary of recent p53 research


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