Mechanism for Epstein-Barr Virus Protein’s
Role In Blood Cancers Discovered
Implications for New Therapeutic Targets for B Cell Lymphomas
and Other EBV-Associated Illnesses
(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
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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