PHILADELPHIA – Researchers at the University of Pennsylvania School of Medicine have shed new light on how Kaposi’s Sarcoma-associated Herpes Virus (KSHV) subverts normal cell machinery to cause cancer. A KSHV protein called latency-associated nuclear antigen, LANA for short, helps the virus hide out from the immune system in infected cells. When LANA takes the place of other proteins that control cell growth, it can cause uncontrolled cell replication.
The findings appear in a recent issue of the Proceedings of the National Academy of Sciences (USA).
“This is the first report of LANA interfering with the crucial cellular protein called intracellular Notch,” says lead author Erle Robertson, PhD, Professor of Microbiology and the Program Leader of Tumor Virology at Penn’s Abramson Cancer Center. Notch is a signaling molecule that triggers cell development and maintains the stability of cells in many organs, such as the brain, heart, blood, and muscle.
“Intracellular notch, or ICN, promotes cell growth and proliferation, therefore it must be regulated so that these processes do not lead to cancer,” says Robertson. “We found that regulation of ICN through binding to another protein called Sel10, a cell-cycle regulatory protein, is derailed. The large complex of ICN, Sel10, and other factors is marked for degradation by a process called ubiquitination,” says Robertson. In normal uninfected cells, the level of ICN, and thus cell growth and proliferation, is fine-tuned by regulating ICN degradation.
LANA interferes with the degradation of ICN because it competes with ICN for the same binding site on Sel10. If LANA sits on Sel10, ICN cannot be degraded and cell growth and proliferation are no longer controlled. Kaposi’s sarcoma and primary effusion lymphoma are two of the viral-associated cancers that are common in immune-compromised patients.
This is the second mechanism discovered by Robertson and his associates by which KSHV subverts control of normal cell growth. Robertson’s group previously found that LANA marks tumor suppressors, such as p53 and VHL, for degradation.
Other herpes viruses, such as the one that causes cold sores and Epstein-Barr virus, which causes mononucleosis, are able to hide out in cells as well. “Whether these latent herpes viruses use some of the same strategies that we have found for LANA in KSHV has not been determined,” says Robertson.
This new role for LANA was discovered using specific human cell lines. The next step is to test whether LANA works the same way in animals infected with KSHV. “We have completed some studies in mice that indicate that LANA can contribute to tumor development in an animal in ways similar to what we have observed in cell culture,” says Robertson. The animal models will be useful for testing new drug therapies that may inhibit the activity of LANA and eventually prevent the growth of viral-associated cancers.
This work was funded by the National Institutes of Health and the Leukemia and Lymphoma Society of America. Co-authors are Ke Lan of Penn and the Chinese Academy of Science, and S.C. Verma, M. Marakami, B. Bajaj and R. Kaul, all from Penn.
The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.
PENN Medicine is
a $3.5 billion enterprise dedicated to the related missions
of medical education, biomedical research, and excellence in
patient care. PENN Medicine consists of the University of Pennsylvania
School of Medicine (founded in 1765 as the nation's first medical
school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the
nation in U.S.News & World Report's survey of top research-oriented
medical schools; and, according to most recent data from the
National Institutes of Health, received over $379 million in
NIH research funds in the 2006 fiscal year. Supporting 1,400
fulltime faculty and 700 students, the School of Medicine is
recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders
of academic medicine.
The University of Pennsylvania Health System includes
three hospitals — its flagship hospital,
the Hospital of the University of Pennsylvania, rated one of
the nation’s “Honor Roll” hospitals by U.S.News & World
Report; Pennsylvania Hospital, the nation's first hospital; and
Penn Presbyterian Medical Center — a
faculty practice plan; a primary-care provider network; two multispecialty
satellite facilities; and home care and hospice.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.