Newswise — A team of research scientists led by Robert S. Haltiwanger, Ph.D., Professor and Interim Chair, Department of Biochemistry and Cell Biology at Stony Brook University School of Medicine, identified a novel gene in flies that if mutated shuts off the Notch receptor. Notch initiates an essential cell-signaling pathway involved in cell differentiation during animal development. The discovery of what the team calls the "Rumi" gene may have important implications in the study of human diseases in which Notch function defects are associated. These include various forms of cancer and developmental disorders of the liver, heart, skeleton and kidney. Their findings are reported in the current issue (January 25) of the scientific journal Cell.
The collaborative team completed experiments showing that Rumi is a protein O-glucosyltransferase (an enzyme that adds sugars to proteins) and regulates Notch signaling by modifying Notch with O-glucose for its proper function in Drosphila, a genus of flies. The researchers found that mutations in Rumi cause a temperature-sensitive Notch phenotype that partly or fully loses its signaling capacity.
"Cell development and differentiation is a complicated biochemical process, but we do know that Notch signaling is essential for cell fate decisions of many types of tissues," says Dr. Haltiwanger. "When there are defects in Notch receptor, those changes lead to developmental defects," he explains.
Regarding the results of the Rumi gene within the research model, Dr. Haltiwanger adds, "Given the evolutionary conservation of the Notch signaling pathway and presence of O-glucosylation in Notch proteins, it is likely that O-glucose is also essential for the Notch function in mammals, including humans."
Based on the concept that O-glucose appears essential for proper Notch functioning, and the research findings with the Rumi mutation, Dr. Haltiwanger believes that the development of drugs that inhibit Rumi may be useful in reducing Notch activity in diseases in which Notch is aberrantly activated. One notable example is in human T cell acute lymphoblastic leukemia. Notch plays a key role in the proper development of T cells. Therefore, defects in Notch are known to cause this form of leukemia.
Dr. Haltiwanger's colleagues an co-authors of the Cell article, titled "Rumi is a CAP10 Domain Glycosyltransferase that Modifies Notch and is Required for Notch Signaling," include: Hideyuki Takeuchi, Ph.D., and Nadia A. Rana, of the Department of Biochemistry and Cell Biology at Stony Brook University; and Hugo J. Bellen, Ph.D., and a team of investigators from the Howard Hughes Medical Institute, Baylor College of Medicine in Houston. The research was supported in part by the National Institutes of Health (NIH), and the NIH's National Institute of General Medical Sciences, as well as by a fellowship of the Astellas Foundation for Research on Metabolic Disorders.
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