St. Jude Children’s Research Hospital investigators have identified a novel structure in cells that serves as a control switch in the body’s system for eliminating damaged cells and also offers new therapeutic potential.
The findings provide fresh insight into the machinery at work as cells ramp up production of p53 protein following DNA damage. The p53 protein plays a critical role in how cells respond to the stress that damages DNA. The gene that carries instructions for making p53 protein is the most commonly mutated gene in human cancers.
Investigators also identified molecules that disrupt the system and reduce p53 protein levels in cells damaged by irradiation or chemotherapy. These small molecules helped cells growing in the laboratory survive better after they were damaged. The findings appear in the September 13 online edition of the journal Genes & Development.
The work lays the foundation for a new approach to protecting healthy tissue using small molecules to reduce p53 protein levels in cells following damage caused by a wide range of factors, including the radiation and chemotherapy used to treat cancer or accidental exposure to dangerous chemicals or radiation, said Michael Kastan, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center and the paper’s senior author. The same approach might also help ease the tissue damage that occurs as blood flow and oxygen are restored following a heart attack or stroke.
“We are excited about this because we now theoretically have a way of blunting p53 induction in settings where it is detrimental,” he said.
The work builds on previous research from Kastan’s laboratory into the mechanics of how p53 protein increases in response to cellular stress and DNA damage. Jing Chen, Ph.D., a postdoctoral fellow in Kastan’s laboratory, is first author of the study.
The jump in p53 protein production was widely attributed to a decrease in the breakdown of p53 inside such cells. But in 2005, Kastan and his colleagues showed that affected cells also produce more of the protein. Researchers reported that after DNA damage, a protein called RPL26 binds to a molecule called p53 messenger RNA, leading to a dramatic rise in p53 protein. Messenger RNA (mRNA) is part of the cell’s protein production machinery that translates the genetic instructions inside cells into needed proteins.
Efforts to better understand how RPL26 functioned led investigators to this latest discovery. Researchers showed that optimal p53 production required RPL26 to bind to a structure in mRNA not previously seen in mammalian cells.
The structure forms when the ends of the normally single-stranded mRNA molecule come together and make a short region of double-stranded RNA. Those ends must obey the rules of RNA pairing and link only with a complementary molecule, or base pair, on the other strand. “We suspect we will find a whole family of stress-related proteins regulated this way,” Kastan said.
Investigators showed that blocking the interaction at either end of the mRNA was enough to short-circuit RPL26 binding and lead to a dramatic fall in p53 protein levels in stressed or damaged cells.
Researchers used short pieces of DNA, so small they were absorbed by cells after simply being added to cell culture, to target the interactive bases and successfully disrupt formation of the double-stranded structure. Restoring the ability of the bases to bind the two ends of the mRNA restored RPL26 binding and stimulated p53 protein synthesis.
Work is underway to develop a mouse model to speed efforts to find or design small molecules that target this mechanism. “We have a long way to go in terms of drug development, but the better we can define the interaction between RPL26 and the double-stranded RNA structure the more likely we will be able to develop other small molecules to specifically block that interaction,” Kastan said.
This research was supported in part by grants from the National Institutes of Health and ALSAC.St. Jude Children’s Research Hospital
Founded in 1962 by the late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world, publishing more research articles than any other pediatric cancer research center in the United States. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance. St. Jude is financially supported by thousands of individual donors, organizations and corporations without which the hospital’s work would not be possible. In 2010, St. Jude was ranked the most trusted charity in the nation in a public survey conducted by Harris Interactive, a highly respected international polling and research firm. For more information, go to www.stjude.org.
Summer Freeman | Newswise Science News
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
23.11.2017 | Information Technology
23.11.2017 | Physics and Astronomy
23.11.2017 | Life Sciences