UNC-CH 'Groucho' Research Offers Insights Into How Embryo, Cancer Cells Communicate

October 21, 1998

By DAVID WILLIAMSON
UNC-CH News Services

CHAPEL HILL - Research on "whiskered" fruit flies containing proteins named after Groucho Marx has uncovered part of the way signaling mechanisms inside cells control what genes produce during normal development.

Because fruit flies and vertebrates, including humans, use essentially identical signals, the findings are a new and likely important step toward understanding how people and animals develop, scientists say. They also could help explain what goes wrong when cancer cells reproduce wildly and contribute to therapies that might reverse that deadly growth.

The research, conducted at the University of North Carolina at Chapel Hill and elsewhere, shows.

Groucho proteins and another family of proteins called Tcf interact to repress cells' internal signaling activity. That activity determines which genes are turned on, thus selecting what internal machinery cells will make. Normally, the process then informs cells what their role in life will be -- whether they will become part of an arm, for example, or part of a kidney.

"If the signaling pathway we are working on, which in fruit flies is called the 'wingless' pathway, is turned on continuously in humans in any of a variety of cell tissues such as in the colon, prostate or brain, that's the first step toward tumor development," said Dr. Mark Peifer, associate professor of biology at UNC-CH. "Our new work, aimed at learning in detail how genes get turned on and turned off normally, shows the process of controlling signals is a step more complicated than we thought.

"In a series of experiments, we found that Groucho and Tcf proteins act together to turn genes off like a light switch," Peifer said. "We already knew from earlier studies that we and others have done that Tcf proteins, when acting with another molecule called 'Armadillo,' turn genes on. Our hypothesis is that something very similar is happening in cancer where beta-catenin, the human version of Armadillo,. works with human Tcf to regulate gene expression.

The long-term goal is a lot more important than knowing how fruit flies develop, the scientist said.

"Ultimately, we want to figure out how to turn off genes inside tumors," he said. "If we can turn them off, that would have therapeutic potential."

A report on the findings appears this month in Nature, one of the two top scientific journals. Besides Peifer, a member of the Lineberger Comprehensive Cancer Center, authors are graduate students Robert A. Cavallo, Rachel T. Cox and Gordon A. Polevoy, all in UNC-CH's Curriculum in Genetics and Molecular Biology. Other authors are Melissa M. Moline and Dr. Amy Bejsovec of Northwestern University and Jeroen Roose and Dr. Hans Clevers of University Hospital in Utrecht, The Netherlands.

The National Institutes of Health and the U.S. Army Breast Cancer Research Program supported the research.

"Three years ago, the Nobel Prize and medicine and physiology went to three scientists who showed us that essentially the same cellular machinery that works in people works in fruit flies," Peifer said. "One of these people was Dr. Eric Wieschaus, with whom I did my postdoctoral work at Princeton.

"Recognition that all animals use the same machinery was really important because it meant we can study that machinery in a model animal like a fruit fly and then apply what we learn directly to humans," he said. "In the fruit fly we have a lot of very powerful experimental tools."

Studying fundamental biological processes like cell signaling gives scientists around the world insights into a variety of human diseases, Peifer said. Experiments on complex subjects such as the one his team investigates only infrequently lead to major breakthroughs, but instead create useful pieces of a large and fascinating puzzle that is becoming increasingly clear.

"Science is a never-ending step-by-step process carried on by lots of people around the world working together, sharing and building on each other's work," he said. "We think our results are one more step forward."
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Note: Peifer can be reached at (919) 962-2271.
Contact: David Williamson, (962-8596).
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University of North Carolina at Chapel Hill

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