|
Mahjong-defective cells (labelled by green) are out-competed by the adjacent normal cells and undergo programmed cell death (labelled by red) both in fruit fly's larval epithelia (left panel) and mammalian cultured epithelial cells (right panel). Image courtesy of Yoichiro Tamori. 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.
|
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.
PLoS Biology has published the
findings, which the researchers describe in their paper "Involvement of
Lgl and Mahjong/VprBP in Cell Competition." The article can be accessed
online at
www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000422.
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.
Florida State
University
