image: The viral protein recruits cellular proteins complexes made for ubiquitination of specific substrates like VHL and p53. Once the Ub portion is attached to the substrates they are then recognized and degraded by the cellular 26S proteasome system. view more
Credit: Erle Robertson, Ph.D., University of Pennsylvania School of Medicine
(Philadelphia, PA) -- Researchers at the University of Pennsylvania School of Medicine have discovered how the Kaposi's sarcoma-associated herpesvirus (KSHV) subverts a normal cell process in order to promote tumor growth. The finding, published in the most recent issue of PLoS Pathogens, offers new potential strategies for treating Kaposi's sarcoma and other cancers associated with viruses.
KSHV is an opportunistic pathogen that rarely affects individuals with normal immune systems. However, HIV/AIDS patients and those who are immune suppressed such as organ transplant patients are at high risk for developing Kaposi's sarcoma and another cancer called primary effusion lymphoma.
The study describes how a KSHV-encoded protein, called latency-associated nuclear antigen, or LANA, tricks the cell into destroying two major suppressors of tumor growth called von Hippel Lindau (VHL) and p53. "In addition, we have shown that when LANA expression was blocked, the tumor suppressors again become stable suggesting a direct role of the viral protein in regulation of these major cell proteins," says lead author Erle Robertson, PhD, Professor of Microbiology and the Director of Tumor Virology at Penn's Abramson Cancer Center.
Marked for Disposal The trick is played out in a cell process called ubiquitylation. This refers to a pathway in all cells whereby a protein aptly named ubiquitin binds to cellular proteins and marks them for degradation. This process can be likened to putting out the garbage for disposal.
Ubiquitylation and degradation involve a complex set of proteins in addition to ubiquitin. "We found that the viral LANA has an amino acid motif that mimics non-viral cell proteins usually involved in the ubiquitylation process," says Robertson. This motif, or stretch of amino acids, normally enables LANA to bind to tumor suppressors p53 or VHL, thus bringing them into the active ubiquitylation complex. Once in the complex, the tumor suppressors are targeted for degradation.
Tumor suppressors, as their name implies, prevent or limit the growth of tumors in numerous ways. One way the tumor suppressors p53 and VHL work is to mark a key protein that controls the blood supply in a tumor mass. Once marked, this protein called hypoxia-induced factor 1a (HIF-1a) is degraded through ubiquitylation before it can start the process of activating genes responsible for inducing growth of more blood vessels to supply the tumor with oxygen. However, in a KSHV-infected cell, p53 and VHL themselves would be targeted for degradation and HIF-1a would then be free to activate genes involved in growth of blood vessels to increase the blood supply to the tumor.
"Use of such proteosome inhibitors as Bortezomib as cancer therapeutic agents has been ongoing for the last four to five years and this study provides crucial step in understanding the mechanism for anti-tumorigenic activity against KSHV-associated human cancers," concludes Robertson. "Additionally, we can now use compounds known to inhibit proteosome activity to determine their effectiveness in inhibiting the Kaposi's viral-induced degradation of these two major tumor suppressors." This, he says, is important in finding or designing drugs that can be specifically used against KSHV, and potentially, other virus-associated cancers.
This work was funded by the National Institutes of Health and the Leukemia and Lymphoma Society. Co-authors in addition to Robertson are Qi-Liang Cai, Jason S. Knight, Suhbash C. Verma, and Philip Zald, all from Penn.
PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality 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 ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. 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, all of which have received numerous national patient-care honors (Hospital of the University of Pennsylvania; 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.
The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation's best in cancer care, according to US News and World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment.
Journal
PLoS Pathogens