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CANCER | July 02, 2009

Suppressing the Suppressor

Researchers pinpoint a new enemy for tumor-suppressor p53.
“Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells.”

Researchers at The University of Texas M. D. Anderson Cancer Center have identified a protein that marks the tumor suppressor protein p53 for destruction, providing a potential new avenue for restoring p53 in cancer cells. P53 normally forces potentially cancerous cells to kill themselves and is shut down or depleted in most human cancers. The new protein, called Trim24, feeds p53 to a protein-shredding complex known as the proteasome by attaching targeting molecules called ubiquitins to the tumor suppressor, the researchers report in the online edition of the Proceedings of the National Academy of Sciences.

“Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells,” says senior author Michelle Barton, a professor in M. D. Anderson's Department of Biochemistry and Molecular Biology.

Studies of the p53 protein and gene tend to focus on cancer cell lines or tumors, where the dysfunction already is established, Barton says. The researchers wanted to better understand the mechanism that regulates p53 and decided to purify it from normal cells.

The team developed a strain of mice with a biochemical tag attached to every p53 protein expressed. After first assuring that the tagged p53 behaved like normal p53, the team then used the tag, or hook, to extract the protein. “We could then identify proteins that were attached to p53, interacting with it, through mass spectrometry,” Barton says. They found Trim24, a protein previously unassociated with p53 that is highly expressed in tumors and is a target of two known oncogenes in distinct forms of leukemia and thyroid cancer.

Subsequent experiments showed that decreased levels of Trim24 led to increased levels of p53 expression in the cell nucleus, and increasing Trim24 expression reduced p53 levels. Loss of Trim24 expression in a breast cancer cell line caused spontaneous programmed cell death or apoptosis. A similar response was confirmed in human lung, colon and prostate cancer cells.

Treating cells with a proteasome inhibitor also led to increased p53 expression. Removing an important binding domain of Trim24 or depleting it completely both led to greatly reduced ubiquitin targeting of p53.

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