Researchers pinpoint a new enemy for tumor-suppressor p53

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 team reported this week in the Proceedings of the National Academy of Sciences Online Early Edition.

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

The discovery is based on an unusual approach to studying p53, which normally forces potentially cancerous cells to kill themselves and is shut down or depleted in most human cancers. Studies of the p53 protein and gene tend to focus on cancer cell lines or tumors, where the dysfunction already is established, Barton said. “We wanted to purify p53 from normal cells to better understand the mechanisms that regulate it.”

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 said.

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 – 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.

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.

Co-authors with Barton are first author Kendra Allton, Abhinav Jain, Ph.D., Hans-Martin Herz, Ph.D., Wen-Wei Tsai, Ph.D., Andres Bergmann, Ph.D., and Randy Johnson, Ph.D., all of M. D. Anderson's Department of Biochemistry and Molecular Biology; and Sung Yun Jung, Ph.D., and Jun Qin, Ph.D., of the Department of Molecular and Cellular Biology at Baylor College of Medicine. Allton completed the paper as her master's degree thesis for The University of Texas Graduate School of Biomedical Sciences, a joint program of M. D. Anderson and The University of Texas Health Science Center at Houston. Allton, Jain, Tsai, Johnson and Barton also are with M. D. Anderson's Center for Stem Cell and Developmental Biology.

Funding for the project was provided by M. D. Anderson's Kleberg Fund for Innovative Research, grants from the National Institutes of Health, CellCentric, Ltd., the Kadoorie Foundation, the Welch Foundation, the National Cancer Institute and the Laura and John Arnold Foundation Odyssey Fellowship (for Abhinav Jain).

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America's Best Hospitals,” a survey published annually in U.S. News & World Report.

Media Contact

Scott Merville EurekAlert!

More Information:

http://www.mdanderson.org

All latest news from the category: Life Sciences and Chemistry

Articles and reports from the Life Sciences and chemistry area deal with applied and basic research into modern biology, chemistry and human medicine.

Valuable information can be found on a range of life sciences fields including bacteriology, biochemistry, bionics, bioinformatics, biophysics, biotechnology, genetics, geobotany, human biology, marine biology, microbiology, molecular biology, cellular biology, zoology, bioinorganic chemistry, microchemistry and environmental chemistry.

Back to home

Comments (0)

Write a comment

Newest articles

Lighting up the future

New multidisciplinary research from the University of St Andrews could lead to more efficient televisions, computer screens and lighting. Researchers at the Organic Semiconductor Centre in the School of Physics and…

Researchers crack sugarcane’s complex genetic code

Sweet success: Scientists created a highly accurate reference genome for one of the most important modern crops and found a rare example of how genes confer disease resistance in plants….

Evolution of the most powerful ocean current on Earth

The Antarctic Circumpolar Current plays an important part in global overturning circulation, the exchange of heat and CO2 between the ocean and atmosphere, and the stability of Antarctica’s ice sheets….

Partners & Sponsors