Removal of a p53 Inhibitor Causes Cancer Cell Death

Cancer researchers employing a novel technique to study the p53 tumor suppressor gene in normal rather than cancerous tissues have identified Trim24 as a p53 inhibitor that may be susceptible to drug treatment.

Tripartite motif-containing 24 (Trim24) also known as transcriptional intermediary factor 1-alpha (TIF1-alpha) is a protein, which in humans is encoded by the Trim24 gene. The protein encoded by this gene mediates transcriptional control by interaction with the activation function-2 (AF-2) region of several nuclear receptors, including the estrogen, retinoic acid, and vitamin D3 receptors. The protein localizes to nuclear bodies and is thought to associate with chromatin and heterochromatin-associated factors.

Investigators at the University of Texas M. D. Anderson Cancer Center (Houston, USA) created a mouse and stem cell model by knock-in (KI) genetic engineering. The new line of mice had a tandem-affinity-purification (TAP) epitope linked to p53. Mass spectrometry of TAP-purified p53-complexes from embryonic stem cells revealed the presence of Trim24, a previously unknown partner of p53.

Results from additional experiments published in the June 25, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) showed that expression of p53 activity was inversely proportional to the levels of Trim24. Trim24 marked the p53 protein with ubiquitin for proteosomal destruction. Complete removal of Trim24 in human breast cancer cells caused p53-dependent, spontaneous apoptosis.

"We wanted to purify p53 from normal cells to better understand the mechanisms that regulate it," said senior author Dr. Michelle Barton, professor of biochemistry and molecular biology at University of Texas M. D. Anderson Cancer Center. "Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells."

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University of Texas M. D. Anderson Cancer Center