A landmark study by Florida State University biologists, in collaboration with scientists in Britain, is the first to identify a life-or-death "cell competition" process in mammalian tissue that suppresses cancer by causing cancerous cells to kill themselves.
Central to their discovery was the researchers' identification of "Mahjong" –– a gene that can determine the winners of the competition through its close relationship with another powerful protein player. Lead author Yoichiro Tamori and Associate Professor Wu-Min Deng of Florida State and Yasuyuki Fujita of University College London named the newfound gene after the Chinese game of skill and luck.
The findings shed light on the critical interactions between cancerous cells and surrounding tissue, and confirm that those interactions occur not only in fruit fly models but also in mammalian cell cultures.
Tamori and team found that Mahjong binds to and interacts with the tumor suppressor gene "Lethal giant larvae" (Lgl). That bond allows Mahjong to influence the outcome of cell competition, because it is mutations in Lgl –– or in genes interacting with it –– that transform a normal cell into a malignant one, triggering the lethal showdown between neighboring healthy cells and cancerous ones."A better understanding of the ways that inherited or acquired mutations in key proteins lead to cell competition should help foster new therapies that increase the odds of victory for normal cells," said Tamori, a postdoctoral fellow in Florida State's Department of Biological Science.
The study began with a focus on Lgl, a gene that normally prevents the development of tumors by tightly controlling cell asymmetry and proliferation. To more fully understand its role in cell competition, the Florida State and University College London biologists looked at Lgl in both fruit flies and mammals. They knew that earlier studies of Lgl's structural qualities had concluded that it worked in tandem with other proteins. To try to identify its possible partners, the researchers used a technique that worked to trap both Lgl and any proteins bound to it.
They learned that Lgl had just one binding partner –– soon to be known as Mahjong.
"In addition to identifying Mahjong and its relationship with Lgl," said Deng, "we confirmed that both genes function in the same pathway ¬¬in both fruit flies and mammals to regulate cellular competitiveness."
To determine if a mutation would induce cell competition in fruit flies, the Florida State biologists modified fly larvae by deleting the Mahjong gene from subsets of the wing-tissue cells.
Then, using a fluorescent probe that can identify cells undergoing apoptosis (a form of programmed suicide), they saw that cell death was occurring in the Mahjong mutant cells that were adjacent to normal cells, but not in those surrounded by fellow Mahjong mutants.
"In competition with their normal neighbors," said Tamori, "cells without Mahjong were the losers."
After Tamori and Deng confirmed the role of Mahjong in fruit fly cell competition, their collaborators at University College London sought to induce competition in mammalian cells.
To replicate as closely as possible the occurrence of mutations caused by environmental factors, Fujita and his team engineered kidney cells whose copies of the Mahjong gene could be shut down by the antibiotic tetracycline. Before adding tetracycline, they mixed the engineered cells with normal ones and allowed them to grow and form tissue.
"When tetracycline was added to the tissue, the cells in which Mahjong had been shut down began to die, just as they had in the fruit fly," Tamori said.
"In the kidney cells, as in flies," he said, "apoptosis was only observed in Mahjong mutants when they were surrounded by normal cells. We now had a clear demonstration of cell competition in mammalian tissue, triggered by mutations in a key protein."
Next, the team sought to prevent apoptosis in cells that lacked Lgl or Mahjong by copying the remaining protein partner in larger-than-normal numbers.
"We learned that overexpressing Mahjong in Lgl-deficient cells, which typically self destruct, did in fact prevent apoptosis," Deng said. "But, in contrast, we found that overexpressing Lgl in Mahjong-deficient cells did not prevent cell suicide."
Funding for the study came from a five-year grant to Deng from the National Institutes of Health (NIH). A developmental and cell biologist at Florida State since 2004, Deng is recognized for research in the model organism Drosophila melanogaster (fruit fly) that has enhanced understanding of gene regulation and signaling pathways linked to cancer and other diseases.
Deng's NIH grant supported another recent study that also has advanced cancer research. In collaboration with scientists from the Johns Hopkins University School of Medicine, Deng and Florida State colleagues studying the "Hippo" tumor suppressor pathway identified an influential new gene there, which they named "Kibra." Their findings were published Feb. 16, 2010, in the journal Developmental Cell and discussed in the April 2010 issue of Nature Reviews Cancer.
Tamori and Deng of Florida State University and Fujita of University College London co-authored the PLoS Biology paper "Involvement of Lgl and Mahjong/VprBP in Cell Competition" with support from a team comprised of a postdoctoral fellow, graduate and undergraduate students, and a technician. From FSU, the team members were Ai-Guo Tian, Yi-Chun Huang, Nicholas Harrison and John Poulton. From UCL, they were Carl Uli Bialucha, Mihoko Kajita, Mark Norman, Kenzo Ivanovitch, Lena Disch and Tao Liu.
Yoichiro Tamori | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering