Researchers at The University of Texas M. D. Anderson Cancer Center report that a protein called Trim24 helps destroy the tumor suppressor p53. They found that it attaches ubiquitins to p53, which signals destruction by proteosomes.
The study is published in the online early edition of the Proceedings of the National Academy of Sciences in a paper titled “Trim24 targets endogenous p53 for degradation.” The work was partially funded by CellCentric.
Trim24 has not been associated with p53, according to the M.D. Anderson team, but is a target of two known oncogenes in distinct forms of leukemia and thyroid cancer. The scientists set out to study p53 in normal cells to better understand the mechanisms that regulate it.
They 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 to extract the protein. “We could then identify proteins that were attached to p53, interacting with it, through mass spectrometry,” explains senior author, Michelle Barton, Ph.D., professor in the department of biochemistry and molecular biology.
Experiments showed that decreased levels of Trim24 led to increased levels of p53 expression in the cell nucleus and vice versa. Loss of Trim24 expression in a breast cancer cell line caused 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 led to greatly reduced ubiquitin targeting of p53. An analogous system in fruit flies showed that a simpler version of Trim24 in the flies plays a similar role regulating p53, demonstrating that the relationship is evolutionarily conserved.
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