(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,"
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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