(Philadelphia, PA) - Earlier this year, researchers at the University of Pennsylvania School of Medicine identified a link between a critical cancer pathway and an Epstein-Barr Virus (EBV) protein known to be expressed in a number of EBV-associated cancers. Their findings demonstrated a new mechanism by which EBV can transform human B cells from the immune system into cancerous cells, which can lead to B-cell lymphomas. Now, they have found that the viral protein--called EBNA3C (for EBV nuclear antigen)--mediates the degradation of the retinoblastoma protein, an important molecular brake for cell proliferation.

Erle S. Robertson, PhD, an Associate Professor of Microbiology who leads the Tumor Virology Program at Penn's Abramson Cancer Center, and MD/PhD student Jason Knight, published their results last week in the Proceedings of the National Academy of Sciences.

The retinoblastoma protein (Rb) is a major regulator of several genes in charge of cell proliferation and cell-cycle regulation. In the nucleus, Rb normally binds to E2F, turning off genes involved with cell proliferation. Using human cell cultures infected with the Epstein-Barr virus, the investigators found that EBNA3C recruits a group of molecules called the SCF complex, which attaches ubiquitin to Rb. This inadvertently tags Rb for degradation by the proteosome machinery, the cell’s recycling plant. With Rb out of the way, the cell now reproduces uncontrollably.
"It's as simple as that, but it's a major mystery solved that many researchers have been working on for at least 15 years," says Robertson.

EBV, a member of the herpesvirus family and one of the most common human viruses, plays a role in cancers such as lymphoproliferative diseases in transplant or AIDS patients, Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma, and also causes the well-known disease infectious mononucleosis. As many as 95 percent of adults 20 years and older have been infected with EBV, but show no symptoms.

Now, the researchers are in the process of blocking the molecular signals caused by EBNA3C's presence in B cells. This points the way to a possible drug for EBV-related cancers. "Stopping this step in the life cycle of EBV could be a major potential target for the development of therapeutics for treating EBV-related B cell lymphomas," says Robertson. "This is especially important because a large percentage of patients are non-responsive to the current frontline drug for treating B cell lymphoma, a CD20 monoclonal antibody." The researchers surmise that the first use of future therapies from these studies could be in lymphoproliferative disease in transplant and immunocompromised patients.

This research was funded by the National Institutes of Health and the Leukemia and Lymophoma Society of America. Nikhil Sharma, a student from Cherokee High School, New Jersey and volunteer at Penn at the time of the study, and now an undergraduate at Johns Hopkins University, was also a co-investigator in this study.

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