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Mac Seafraidh
Tuesday, December 14th, 2004, 01:05 AM
The war against cancer focuses on a key gene

By ROBERT S. BOYD

Knight Ridder Newspapers


WASHINGTON - In the long, frustrating battle against cancer, one gene has emerged as a key, both to the cause of the disease and to its prevention.

This master gene watches out for cells whose DNA has been corrupted by tobacco smoke, ultraviolet light, toxic chemicals or other carcinogens. If it detects a damaged cell, it triggers a process that blocks that cell from reproducing and possibly giving birth to a malignant tumor. But if the gene itself is defective, it can't do its job. Cancer is often the result.

The gene's official name is "p53," but some scientists call it the "guardian of the genome," the sum of all 25,000 or so genes in the human body.

"You can call p53 the guardian because it's the common denominator in virtually all human tumors," said Bert Vogelstein, a leading cancer expert at the Johns Hopkins Medical Institutions in Baltimore. "It's almost impossible to develop cancer in most organs unless p53 is inactivated."

Researchers are looking for drugs that can restore damaged p53, so it can get back to its job of defending us against cancer.

"A number of mechanisms are now being explored to use p53 to kill tumor cells," Karen Vousden, a cancer researcher at the University of Glasgow, Scotland, said in an e-mail message.

The gene has been the subject of more than 300,000 scientific reports since it was discovered 25 years ago. The flood of papers, which even some experts find daunting, shows no sign of abating.

"As one of our key defenses against cancer, p53 lies at the heart of a massive research effort that has generated an avalanche of papers," Vousden said.

A collection of reports summarizing the state of p53 science appeared in a special edition of the journal Nature on Nov. 18.

The research "is helping to define the roots of malignancies and shows promise for the development of better cancer therapies," wrote Joan Massague, a cancer biologist at the Memorial Sloan Kettering Cancer Center in New York. "Recent progress in these areas is so extensive."

Despite this vast scientific effort, the details of how p53 works are still imperfectly understood, according to Scott Lowe, a cancer specialist at the Cold Spring Harbor Laboratory on Long Island, N.Y.

"We have only recently begun to glimpse the diversity and complexity of (these) mechanisms," Lowe said.

A gene such as p53 - a little strip of DNA in the nucleus of the cell - can't do anything on its own. Instead, it contains the instructions to produce a protein - a chain of molecules in the outer body of the cell - which performs the actual work. The protein is also called p53.

The p53 gene and its protein are the hub of a complex network of other genes and proteins that act as a team to detect and prevent cancer. Members of the network cooperate to stop a flawed cell from dividing in order to allow other proteins to try to repair the damage. If that can't be done, p53 triggers a form of cell suicide known as apoptosis, eliminating the risk that the cell will turn cancerous.

In effect, p53 acts as a "supreme judge" that decides the fates of cells and guarantees their good behavior, as a Russian scientist, P.M. Chumakov, once described it.

"These tumor-suppressing mechanisms are remarkably effective," Lowe wrote in Nature. "On average, cancers arise less than once in a human lifetime, despite trillions of potential target cells, each harboring hundreds of susceptible, cancer-causing genes, all subject to a significant mutation rate."

The core of the process is the cell cycle. This is a series of four steps every cell must pass through before it divides to produce two new cells, an essential act in life.

During one of these steps, known as G1, the process halts briefly, giving time for the p53 network to detect errors in the DNA. Later, a second delay, known as G2, is when the cell decides whether it should continue dividing, repair itself or commit suicide.

"We are only just beginning to understand how the cell cycle works," Massague said.

Discovered in 1979, the p53 gene consists of 2,538 chemical units strung along chromosome 17 in the cell's nucleus.

Similar genes are found in creatures from mammals, fish and birds to worms and flies, indicating that control of cell division was crucial throughout evolution.

On the Web:

For more information on the Web, go to http://p53.curie.fr

http://www.centredaily.com/mld/centredaily/news/10407740.htm

StrÝbog
Tuesday, December 14th, 2004, 04:53 PM
The gene's official name is "p53," but some scientists call it the "guardian of the genome," the sum of all 25,000 or so genes in the human body.

Actually, most estimates range from 30,000 to 40,000 genes, depending on how one counts regions coding for small RNAs and such.

This article also fails to mention that the main way in which p53 does all of this is to activate p21, in order to cause cell cycle arrest after DNA damage is detected.