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!
More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn
How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
19.01.2018 | Materials Sciences
19.01.2018 | Health and Medicine
19.01.2018 | Physics and Astronomy