Tumor-Suppressor Regulation May Provide Anticancer Strategy

Genetically modified mice convinced scientists that it was time to rework the widely held beliefs about how a powerful tumor-suppressor called p53 is controlled in cells. A new model of p53 regulation recently developed has significant implications for the development of anticancer therapies.

The study of this new model, published in the April 2006 issue of the journal Cancer Cell, stresses the independent role of two proteins, called Mdm2 and Mdm4. Both proteins are part of the strongly controlled system of checks and balances ensuring that p53 keeps a firm control on unchecked cell growth but does not create chaos in healthy cells.

Up to now, researchers thought Mdm2 and Mdm4 worked together to suppress the activities of p53. As a powerful tumor-suppressor, p53 activates genes that either stop cell division, to allow time for repair of damaged DNA, or, when all restoration attempts prove useless, order the cell to commit suicide, or apoptosis. These mouse studies, conducted by researchers at the Salk Institute for Biological Studies (La Jolla, CA, USA) demonstrated that, indeed, it is Mdm4 that causes p53 to be inactive, while Mdm2 mostly controls the stability of p53's structure.

This distinction is important, according to the study's lead investigator, Geoffrey M. Wahl, Ph.D., a professor in the gene expression laboratory at Salk. "p53 is disarmed in more than half of all cancers, and Mdm2 and Mdm4 are overexpressed to act like cancer-causing oncogenes in much of the rest. We need to know how each of these p53 inhibitors work in normal cells before we can figure out the most effective therapeutic strategies to manipulate them in cancer cells,” he said.

The new findings suggest that cancer drugs now being tested that inhibit Mdm2 may not work as predicted. Researchers thought that, because the functions of Mdm2 and Mdm4 were linked, it would be sufficient to inhibit Mdm2 to restore p53's tumor-suppressing activity in cancer cells.

"In fact, we observed that a partial decrease in Mdm2 or Mdm4 activity only marginally affects p53 function, but that a combined decrease of Mdm2 and Mdm4 dramatically increases p53 function to improve tumor suppression,” remarked lead author Franck Toledo, Ph.D., a former Salk scientist now at the Pasteur Institute (Paris, France). "We also found that the complete ablation of Mdm4 activity leads to very efficient tumor suppression. The clinical implications of these findings are obvious: drugs that inhibit Mdm4 need to be actively searched for, as they should be powerful tools against cancer.”

Researchers already knew that Mdm2 and Mdm4 were important for controlling p53, but how these enzymes interacted with p53 has been a controversial topic. The Salk researchers discovered that the main role of Mdm2 is to tag p53 for destruction to keep p53 protein levels low, whereas Mdm4 prevents p53 from activating genes when the tumor-suppressor is not needed. For p53 to be activated, Mdm4 first needs to be eliminated.

Dr. Wahl and coworkers now think that DNA damage triggers the release of specific enzymes that modify Mdm2 and Mdm4. This mechanism turns on a "switch,” inducing Mdm2 to target both Mdm4 and itself for destruction. Then, as p53 triggers genes to shut down the cell cycle, it also activates the gene for Mdm2. Increased p53 activity leads to heightened expression of Mdm2, which increases degradation of Mdm4--allowing p53 to function unimpeded--at the same time keeping p53 from spiraling out of control.

"This is a very elegant system, because it acts to titrate p53, giving the cell time to repair its DNA, and to gauge how much damage there really is,” observed Dr. Wahl.



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Salk Institute for Biological Studies