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.
Scott Merville | EurekAlert!
New photocatalyst speeds up the conversion of carbon dioxide into chemical resources
29.05.2017 | DGIST (Daegu Gyeongbuk Institute of Science and Technology)
Copper hydroxide nanoparticles provide protection against toxic oxygen radicals in cigarette smoke
29.05.2017 | Johannes Gutenberg-Universität Mainz
The world's highest gain high power laser amplifier - by many orders of magnitude - has been developed in research led at the University of Strathclyde.
The researchers demonstrated the feasibility of using plasma to amplify short laser pulses of picojoule-level energy up to 100 millijoules, which is a 'gain'...
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
29.05.2017 | Earth Sciences
29.05.2017 | Life Sciences
29.05.2017 | Physics and Astronomy