May 31, 2004 Researchers from the Johns Hopkins Bloomberg School of Public Health and other institutions have identified a new target of a cancer-causing gene. The new target of the Ras oncoprotein is an enzyme required to produce a molecular anchor that allows certain proteins to stick to the cell surface. These molecules, known as GPI-anchored proteins, regulate the way cells interact and connect with one another. GPI-anchored proteins are also used by parasites, such as the Plasmodium that causes malaria, to protect themselves against the body's immune defenses. The discovery may provide a new understanding of how tumor cells become malignant and how parasites defend themselves against the body's immune system. The findings, which are published in the May 28, 2004, issue of the journal Cell, could open new avenues of research in the development of treatments for cancers and parasitic infections.
"Scientists have known for many years that Ras proteins work as molecular 'on/off' switches that can change the way cells grow, and interact with other cells. Mutated forms of Ras that are locked in the 'on' position are involved in about 30 percent of all human cancers. Our study identifies a new way in which these forms of Ras may drive tumor progression," said David Levin, PhD, co-author of the study and a professor in the Department of Biochemistry and Molecular Biology at the Bloomberg School of Public Health.
For their study, Dr. Levin and his colleagues observed Ras interaction with an enzyme required for the synthesis of GPI-anchors in yeast cells. They found that yeast Ras inhibited the enzyme, thus interfering with the production of cell surface GPI-anchored proteins. In a Ras-driven cancer cell, such regulation of cell surface proteins may enable individual cells to break away from the primary tumor, a key to the spread of cancer to distant sites. Dr. Levin explained that parasites produce GPI-anchored cell surface proteins as a way to defend against the host's antibodies. Further research is planned to determine if production of GPI-anchored proteins is similarly regulated in animal and parasite cells.
"If Ras regulates the production of GPI-anchored proteins in cancer cells, drugs can be designed to interfere with that regulation and prevent the cancer from spreading," said Dr. Levin.
The authors of "Yeast Ras Regulates the Complex that Catalyzes the First Step in GPI-Anchor Biosynthesis at the ER" include Andrew K. Sobering and Martin J. Romeo, of the Department of Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health. Reika Watanbe and Howard Riezman are with the University of Geneva. Benjamin C. Yan and Peter Orlean are with the University of Illinois. Charles A. Specht is with the Boston University School of Medicine.
Funding was provided by grants from the National Institutes of Health, National Cancer Institute, Human Frontiers Science Program Organization and the Swiss National Science Foundation.
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