Molecular 'brake' found for neurofibromatosis 1

June 22, 2006

DURHAM, N.C. - A team led by Duke University Medical Center researchers has identified in yeast a molecular "brake" that could inhibit the proliferation of cells that characterizes neurofibromatosis 1, a common hereditary disorder that causes potentially troublesome tumors along nerve fibers.

This brake is a protein that appears to stop the cascade of molecular events that leads to the activation of a cancer-producing gene, or oncogene, that causes the tumors. The oncogene, called Ras, was one of the first oncogenes ever discovered and has been implicated in more than half of all human cancers.

The new finding could have important medical implications, the researchers said, since the gene involved and the processes that regulate its activation are the same in humans as in yeasts. Similar genes in different species are known as homologs.

The researchers reported their findings in the June 23, 2006, issue of the journal Molecular Cell. The study was supported by the National Institutes of Health, the Children's Tumor Foundation, and the Department of Defense's Neurofibromatosis Foundation.

Neurofibromatosis 1 occurs in about one in 3,500 newborn children and is characterized by multiple growths, or neurofibromas, on or under the skin, usually along nerve fibers. Occasionally, the neurofibromas become large and disfiguring, or develop on the brain or spinal cord. About half of patients with neurofibromatosis 1 have learning disabilities.

The Duke researchers focused their attention on the neurofibromatosis 1 gene, which contains the blueprint for the production of neurofibromin, a protein found primarily in nerve cells. A tumor-suppressor protein, neurofibromin keeps the Ras gene in check and prevents abnormal cell growth.

"We know that patients with neurofibromatosis 1 have defects, or mutations, in the neurofibromin gene," said lead researcher Joseph Heitman, M.D., Ph.D. "As a consequence, the protein it produces becomes unstable and can no longer effectively suppress the Ras oncogene. As a result, Ras becomes over-stimulated, and this in turn leads to the formation of the tumors along the nerve fivers."

Scientists have not fully understood how and why the mutated neurofibromin gene leads to activation of the Ras oncogene. In the current study, the researchers discovered two novel proteins that appear to be necessary in neurofibromin's ability to regulate Ras. The team named these novel proteins Gpb1 and Gbp2.

"When the two proteins are present, they keep the yeast neurofibromin homologs stabilized, effectively blocking the molecular signaling pathway that activates Ras," said Toshiaki Harashima, Ph.D., first author of the study. Harashima, a cell biologist, worked as a senior postdoctoral fellow in Heitman's laboratory and now is at the National Institute for Basic Biology in Japan.

"Our findings add to basic understanding of how neurofibromin is stabilized," Harashima said. "By shedding light on these fundamental processes, we hope we can help in the development of new drugs or therapies to block the activation of Ras and prevent this disease."

According to Heitman, yeast, a member of the fungus family, can serve as an effective model for studying basic molecular processes in humans, beyond those involved in neurofibromatosis 1, because the signaling pathways of many genes are remarkably similar in both types of organisms.

"These processes have remained in the genomes of yeasts and humans over a billion years of evolution," Heitman said. "Now that scientists have mapped the entire genome of the baker's yeast we study, Saccharomyces cerevisiae, we are able to look for human gene equivalents using all the latest experimental methods that have been developed over the years using yeasts."
-end-
Other members of the team were Scott Anderson and John Yates, from the Scripps Research Institute. They performed mass spectrometry studies that enabled the team to identify the yeast neurofibromin homologs as targets of the Gpb1 and Gpb2 proteins.

Duke University Medical Center

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