Researchers at Hopkins uncover suicide mechanism in damaged cells Discovery could lead to improvements in use of chemotherapy, radiation


NEW YORK -- Cracking a long-standing mystery about human cells' defense against tumors, scientists at the Johns Hopkins University have discovered the probable means by which most cells, when genetically damaged, will kill themselves rather than grow into a tumor that threatens the whole organism.

The suicide mechanism is genetically disabled in many cancer cells, particularly those resistant to chemotherapy and radiation.

These treatments are thought in many cases not to kill cancer cells directly but to cause damage that prompts the cell to kill itself.

Understanding the nature of a cell's suicide procedure may lead to improvements in the use of chemotherapy and radiation.

The finding is also important because it explains the relationship between two major areas of cancer research: cell suicide and the tumor suppressor gene known as p53.

The new research is reported in the current issue of Nature from the laboratory of Dr. Bert Vogelstein and Dr. Kenneth Kinzler, leading experts in the genetics of colon cancer. Dr. Kornelia Polyak is the first author of the report.

"This is a valuable enterprise, and I would give these guys credit in saying they have taken an important step forward," said Dr. Tyler Jacks, a cancer biologist at the Massachusetts Institute of Technology who has been working on the same problem.

He said that the suicide weapon proposed by the Hopkins team was plausible and that if the process of cell suicide could be understood in detail, "it is possible it could be manipulated in more sophisticated ways."

Biologists have known for several years that the integrity of a cell's genetic instructions is watched over by a remarkable piece of biological machinery, a patrolling abort mechanism known as p53.

When the p53 protein detects that the cell's DNA is damaged, it will either prevent the cell from dividing or cause it to disintegrate into a lifeless blob.

P53 and cell death are two of the most active areas of cancer research, yet no one until now has figured out just how p53 pulls the trigger on an aberrant cell.

The answer turns out to be that p53 invokes an ancient enemy of living cells: the intense toxicity of ionized or hyperactive oxygen.

The p53 protein is known to work as a genetic switch, binding to various sites along the DNA of cells and switching on nearby genes, a process called transactivation.

"We have always felt that the ability of p53 to transactivate genes was going to be the key to all of its functions because that ability is abrogated in almost all the mutations of p53 seen in tumors," Vogelstein said.

Polyak set out to identify all the genes that are activated by p53.

She found that a large number produce proteins that increase the amount of free radicals in the cell. These are ionized small molecules, mostly the byproducts of oxygen, that are extremely damaging because they attack DNA and structural components of cells.

A particular target is the mitochondria, structures within the cell that produce its energy. The collapse of the mitochondria then sets off the death of the cell.

Pub Date: 9/23/97

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