Enzyme's Cancer-promoting Activities Linked To Inactivation Of 'Genome Guardian'

The gene p53 prevents a damaged or stressed cell from dividing, said Dr. Lawrence A. Donehower, professor of molecular virology and microbiology and molecular and cellular biology at BCM. When these damaged cells cannot reproduce, they cannot repeat the genetic changes that have led to their damage. In the research described in this report, he and his colleagues describe how WIP1 interacts with both p53 and its off-switch, a protein called Mdm2.

"In the cell, p53 helps to repair cell damage by eliminating those cells with damaged or mutated DNA," said Donehower. "Once that task is accomplished, Mdm2 builds up and turns off p53, bringing the situation back to normal."

"After p53 has finished its activity, WIP1 removes a phosphate molecule, which allows Mdm2 to degrade the p53," said Donehower. However, when WIP1 is overexpressed, meaning there is extra enzyme in the cell, it stabilizes Mdm2, increasing the rate of p53 degradation.

The fact that WIP1 is increased in some breast, ovarian and brain tumors buttresses its role in causing cells to become cancerous, said Donehower.

"In some tumor types, if you have WIP1 overexpression, the prognosis is poorer than if you don't," he said. In fact, tumors with high levels of WIP1 rarely have mutations in p53, he said.

"If you have a lot of this protein in the cell, it's continually knocking down p53. The tumor doesn't need to mutate the p53 gene," he said.

Others who took part in this research include Xiongbin Lu, Ou Ma and Thuy-Ai Nguyen, all of BCM, Stephen N. Jones of the University of Massachusetts Medical School in Worcester, and Moshe Oren of the Weizmann Institute in Rehovot, Israel.

Funding for this research came from the National Institutes of Health, the A-T Children's Project and the U.S. Department of Defense Breast Cancer Research Program.