Doctors find genetic trigger for malignancy Hopkins, Baylor research reported


Researchers from Baltimore and Houston may have explained how one of the most common genetic defects triggers malignant change in cells.

Working from different directions, but together, Dr. Bert Vogelstein of Johns Hopkins University and Drs. Wade Harper and Stephen Elledge of Houston's Baylor College of Medicine, both identified a gene that appears to block cell division and growth.

Drs. Elledge and Harper named their gene CIP1; Dr. Vogelstein named his WAF1. Each group has published a paper on the research in today's issue of the journal Cell.

Because they were looking at the gene in different ways, neither realized that they had found the same piece of DNA until Dr. Elledge called Dr. Vogelstein to discuss the genetic puzzle.

Dr. Elledge was looking at a chemical called cyclin-dependent kinase II, which promotes the growth and division of cells. The gene works to block this enzyme, said Dr. Elledge.

"For the first time, we had identified a negative regulator of cell cycles," he said.

"We were curious about whether this gene was mutated in tumor suppressor genes," he said.

Dr. Vogelstein was working on a gene called p53 that had already been identified as a "tumor-suppressor" -- one that blocks uncontrolled cell division. If it is missing or mutated, cells can divide wildly, potentially changing into malignant growths.

Defective p53 genes have been found in about 50 percent of human cancers.

He and others in his lab had identified a gene that was turned on by p53 and called it WAF1. In his discussions with Dr. Elledge, he determined that the genes were the same.

As Dr. Elledge describes it, the Baylor team was looking at the problem from the bottom up and the Johns Hopkins group looked at it from the top down. "The gene p53 turns CIP1 on and, in turn, that gene blocks cell cycle progression," he said.

Coincidentally, while Drs. Elledge, Harper and Vogelstein were looking at cell-control genes, another pair of Baylor scientists, Drs. James R. Smith and Olivia Pereira-Smith identified the same gene during their studies of aging cells. They named their discovery SDI1 and filed a patent application on it.

When cells are grown in the laboratory, they divide for a time and then stop. The Smiths determined that they must produce a substance that stops DNA synthesis.

Using sophisticated techniques of molecular biology, they finally identified the gene that was stopping it.

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