CELLULAR BIOLOGY
Protein found to play key role as regulator of cell growth and division

Jim Barlow, Life Sciences Editor
(217) 333-5802; b-james3@uiuc.edu

2/1/2001

CHAMPAIGN, Ill. -- A protein located in the cytoplasm between a mammalian cell membrane and nucleus is more important than previously believed. It shuttles in and out of the nucleus as part of a "nuclear experience" that helps regulate cell growth and division, University of Illinois scientists say.

The presence of FKBP12-rapamycin-associated protein (FRAP) in the nucleus previously was considered an artifact of research. New research now indicates that the protein regulates signal transduction, a membrane-to-cytoplasm communication network that governs cellular response to outside stimuli such as growth factors, hormones or foreign agents. If FRAP fails to briefly enter and exit the nucleus, then some crucial proteins fail to synthesize.

"What we found is a brand new mechanism for cell signaling, a fundamental one that was not realized until it was shown in yeast," said Jie Chen, a UI professor of cell biology. "Our research is the first to show this activity in mammalian systems."

A similar finding involving a different protein in yeast cells was published in 1999 in the journal Cell by Harvard Medical School researchers. The two reports taken together, Chen said, offer new insight on the regulation of the protein-synthesis machinery in living cells. The report by Chen and UI graduate student Jae Eun Kim appeared in the Dec. 19 issue of the Proceedings of the National Academy of Sciences. The National Institutes of Health and American Heart Association funded the research.

"This knowledge is important because of the link to human diseases, especially cancer, which are basically cases of cell growth gone awry," she said. "What we have found is a regulatory mechanism for normal cell growth. If we understand normal cell growth better, we can come up with better ways to fight deregulated cell growth."

The idea that FRAP could enter the nucleus on its own, especially considering its size, simply had been dismissed until new molecular technologies opened new research doors, Chen said. Using cultured kidney cells from humans and monkeys, UI researchers found that when they administered leptomycin B, a drug that blocks the export of material out of the nucleus, the protein was found inside.

Without FRAP, signal transduction was blocked. Next, Chen and Kim genetically engineered FRAP to allow them to manipulate the proteinÕs ability to go into and out of the nucleus to test the impact on signaling within the cells. Enhancing protein export led to a decrease of signaling downstream in the network. With protein import enhanced, researchers saw elevated signal transduction.

"FRAPÕs just going into the nucleus is not good enough," Chen said. "This protein has to shuttle between the nucleus and the cytoplasm to function. It has to have a nuclear experience to function in the cytoplasm."