"Essentially, we found a way to grease the gears that drive the interferon signal," says Michael J. Holtzman, M.D., the Selma and Herman Seldin Professor of Medicine and director of the Division of Pulmonary and Critical Care Medicine.
The researchers modified the structure of a protein called Stat1, which relays signals from interferon at the cell surface to genes in the cell nucleus. The modification up shifted Stat1's response to interferon.
The study will appear in the October 7, 2005 issue of the Journal of Biological Chemistry and was selected as the journal's Paper of the Week, which recognizes the top one percent of the journal's papers in significance and overall importance.
The development of a mechanism to tweak Stat1's responsiveness may prove particularly useful for patients with such disorders as hepatitis C, multiple sclerosis and many types of systemic cancer, who currently benefit from interferon treatment, but sometimes find it difficult to tolerate the side effects of the high doses required.
"We reasoned that if we could enhance the way interferon produces its beneficial defensive effects, the body could respond to its normal level of interferon and receive enhanced benefit without side effects," Holtzman says.
The group engineered a mutant Stat1 protein in which the identities of two amino acids were switched. Investigations conducted on cells growing in culture showed that the altered Stat1 proteins reacted more efficiently to the presence of both type I and type II interferons. Further tests revealed that the souped-up Stat1 recruited more of a specific protein it needs to pass on the interferon signal, essentially raising the spee
Source:Washington University School of Medicine