Scientists ID Possible Cancer-Causing Gene

The work involves fruit flies but could benefit people

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HealthDay Reporter

THURSDAY, Aug. 11, 2005 (HealthDay News) -- Looking at genes in the lowly fruit fly, researchers say they've found one that might play a role in human cancer and could become a target of treatment or prevention.

It's not an outrageous idea, said lead researcher Duojia Pan, whose group reported the finding in the Aug. 12 issue of the journal Cell. That's because, on the genetic level at least, humans are remarkably similar to fruit flies.

"Two thirds of the genes in humans are found in fruit flies," said Pan, an associate professor of molecular biology and genetics at the Johns Hopkins Institute for Basic Biomedical Sciences.

And the fruit fly gene in question, which codes for a protein the researchers called Yorkie, has a direct counterpart in humans.

That counterpart -- called YAP -- seems to play the same role, suggesting that in humans, a defect in the gene that makes YAP might contribute to cancer.

In the fruit fly, the Yorkie gene regulates the size of organs, making it a primary culprit as a cancer-causing gene, Pan said.

"If organ size is not regulated properly, you have cancer," Pan said, adding that a mutation in a gene that regulates organ size can cause that kind of malignant overgrowth.

The new research showed that fruit flies missing a gene called hippo developed tumors. That research revealed a tumor-suppression pathway involving proteins made by hippo and two other similar genes, all of which function to chemically add phosphate to other proteins, a process called phosphorylation, the researchers said.

"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.

That other protein appears to be Yorkie, the researchers said. Pan and his colleagues showed that phosphorylation could be stopped by adding a phosphate group to the Yorkie protein. But when the scientists reduced levels of hippo and other proteins that keep Yorkie in check, the protein caused tissues to keep growing by triggering more cells to grow and fewer to die -- the hallmarks of cancer.

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.

The Yorkie discovery is the latest in a series of investigations that Pan started at the University of Texas Southwestern Medical Center at Dallas and is continuing at Johns Hopkins.

"That pathway is conserved from fruit fly to mouse to human," said Jianbin Huang, an instructor in molecular biology at the Texas center who was a member of Pan's research team there.

Huang and his colleagues are working with mice to get more details on the pathway and its possible role in cancer. But he noted that "Yorkie is a homolog of YAP."

Pan has moved into studies of the human gene. "We are looking at tissue samples of cancer cells to see if they express more of this protein than normal cells," he said. "We are screening collections of human cancer cells and tissues to see if there is overexpression."

If cancer cells are found to produce excess amounts of the YAP protein, the question then becomes, "is this causative?" Pan said. "If overexpression is responsible for the cancer, then if we reduce the amount of the protein, we can reverse the cancer process."

But the effort to identify the specific genetic signals responsible for cancer is just beginning, he said.

More information

The state of the art in cancer genetics is described by the National Cancer Institute.

SOURCES: Duojia Pan, Ph.D, associate professor of molecular biology and genetics, Johns Hopkins Institute for Basic Biomedical Sciences, Baltimore; Jianbin Huang, Ph.D, instructor in molecular biology, University of Texas Southwestern Medical Center at Dallas; Aug. 12, 2005, Cell

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