Johns Hopkins scientists have identified
a protein in fruit flies whose counterpart
product in humans may help cause
cancer. The researchers report in the Aug.
12 issue of Cell that a protein dubbed Yorkie
directly controls the fruit fly's organ size
and, when overabundant, causes increased
cell growth and decreased cell death, hallmarks
of cancer. Yorkie's relative in mammals,
called YAP, appears to do the same
thing, the researchers report, which suggests
that in humans, a defect in the gene that
makes YAP might contribute to cancer.
"Over the past few decades, science has
identified a few so-called oncogenes, whose
protein products act as accelerators and trigger
abnormal cell growth," said Duojia Pan,
who carried out most of the study at the
University of Texas Southwestern Medical
Center at Dallas before coming to the Johns
Hopkins Institute for Basic Biomedical Sciences.
"YAP seems to be another one, and
our lab is already investigating the amount
of YAP protein in human tumors to see if
excessive amounts are there."
The researchers also report that Yorkie
directly regulates the size of all the fruit
fly's organs. "We were surprised to find that
by adding Yorkie to levels above normal,
the fruit fly's organs grew larger," Pan said.
"Likewise, by removing Yorkie to levels
below normal, the fruit fly's organs were
smaller than usual."
The new findings build on Pan's earlier
studies, which showed that fruit flies missing
a gene called hippo developed tumors.
That study revealed a tumor-suppression
pathway involving proteins made by hippo
and two other like-minded genes, all three
of which function in a chain reaction to
chemically add phosphate to other proteins,
a process called phosphorylation.
"From those results, we predicted that
another protein must be involved in the
tumor-suppression pathway that is a target
of the phosphorylation cascade," Pan said.
Yorkie turns out to be that "mystery
protein," the researchers report. In their
experiments, Pan and his colleagues show
that the hippo phosphorylation cascade,
by adding a phosphate group to the Yorkie
protein, turns it off.
When the scientists engineered reduced
levels of hippo and other proteins that keep
Yorkie in check, Yorkie caused tissues to
overgrow by prompting more cells to grow
and fewer to die, the hallmarks of cancer.
Further experiments in the fruit fly that
replaced Yorkie with YAP showed that the
proteins play similar roles, suggesting YAP
might participate in a tumor-related pathway
Pan is now trying to identify the signal
that tells genes like hippo to turn on or off
once an organ grows to the appropriate size.
That signal could be harnessed for therapeutics
The study was funded by the National
Institutes of Health.