First step along possible new avenue of cancer research reported

Researchers at Georgetown University have identified a surprising molecular link between two mammalian proteins of very different types. They report in a recent issue of the journal Science that a protein whose major function is to help maintain the structure of a cell and a protein responsible for sending communications signals through a cell are interrelated in an unexpected way. This finding may have broad implications leading to new avenues of research aimed at understanding how different organs develop in the embryo and may even suggest new ways to approach the treatment of cancer.

Lopa Mishra, MD, associate professor of Medicine at Georgetown and colleagues inactivated or "knocked-out" a structural protein gene known as beta spectrin. This gene has numerous functions, including that of supporting a cell's outer membrane in a manner not too dissimilar from the way the metal ribs buttress an umbrella. The Georgetown researchers observed that mice with malfunctioning beta-spectrin genes had many defects in the embryonic development of the heart, brain and other organs.

Surprisingly, they found that abnormalities in the gene encoding for beta-spectrin also interferes with some functions of TGF-beta, a messenger and control protein involved in setting into motion biological programs involved in growth and embryonic differentiation such as the creation of bone and muscle as well as many types of cancer.

Without beta-spectrin, Dr. Mishra reports, a key molecular link which turns on a battery of genes important to development does not occur. This happens, she found, because proteins do not attach to the "ribwork" or inner skeleton of the cell.

This research in mice has important implications for human disease research and treatment, according to Georgetown's Dean of Research and Translational Science Michael Zasloff, MD, PhD. "At the minimum we must now assume that certain diseases of man could arise through mutations in beta-spectrin that alter the types of interactions highlighted by Dr. Mishra. These mutations could very well look a lot like defects in the protein TGF- beta, but you would never think to look at beta-spectrin, prior to this work. Other the other hand, specifically interrupting the interactions of beta-spectrin in the TGF pathway could represent a new approach to the treatment of cancer and disorders involving the overexpression of TGF- beta."

Co-authors of the paper are Yi Tang, Varalakshmi Katuri, Allen Dillner and Bibhuti Mishra of Georgetown University and Chu-Xia Deng of the Genetics of Development Branch of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

This study was funded by NIH, the Veterans Administration, the Betty and Harry Myerberg Foundation, and the Elisabeth and John Cox Foundation.

Georgetown University Medical Center includes the nationally ranked School of Nursing & Health Studies, the School of Medicine, and the Lombardi Cancer Center. The Lombardi Cancer Center is one of only 40 National Cancer Institute-designated comprehensive cancer centers in the nation, and the only one in the Washington DC area. For more information, visit www.georgetown.edu/gumc.

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