Our laboratory works on Epstein Barr virus (EBV) and its role in carcinogenesis
EBV infection is associated with a number of human malignancies: Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease and lymphomas in transplant patients. The vast majority of the human population has been infected with EBV, which maintains a persistent infection in its host. Although EBV is carried by 80% - 90% of adults in a latent form, it only rarely causes cancer. Understanding the mechanisms by which EBV transforms a normal cell into an uncontrolled, proliferating cancer cell is therefore likely to lead to fundamental insights into the process of cancer causation.
In the laboratory, B-lymphocytes purified from the blood of human donors can be infected with EBV. Infected cells become transformed and undergo a process known as immortalization whereby they can multiply indefinitely, similar to cancer cells. We have devised techniques to introduce mutations or changes into the genetic structure (the DNA) of EBV. By infecting B cells with the mutated EBV and observing the effects on EBV replication and B cell transformation, the function of specific EBV genes can be discovered. We have applied these methods to study several latent and lytic EBV genes.
A major area of interest in our laboratory is the process of EBV reactivation and gene regulation. While EBV is usually latent, it periodically begins to replicate lytically and is transmitted from person to person. There is evidence that EBV reactivation is much more common in people with suppressed immune systems, such as those who develop EBV-associated lymphoma. Ongoing work in our laboratory has identified an EBV gene expressed during reactivation that shuts off some host cell functions while simultaneously enhancing EBV gene expression. This gene, SM, appears to perform these functions by binding and regulating the expression of messenger RNA. We have demonstrated that SM both stabilizes and facilitates nuclear export of target mRNAs. Since SM is a shuttling protein, it is likely to act as a molecular chaperone to enhance nucleo-cytoplasmic transport of specific mRNAs. Future research is aimed at identifying novel cellular proteins that SM interacts with in order to regulate gene expression.
We have also cloned and characterized the homolog of SM in Kaposi’s sarcoma-associated herpesvirus (KSHV), another oncogenic herpesvirus that infects B lymphocytes and endothelial cells. We are currently characterizing mutant viruses we have constructed to understand the role of this protein in KSHV biology. The ultimate goal of these molecular studies is to understand the processes by which EBV and KSHV alter the function of infected cells and the means by which they are normally kept in check. Such an understanding at the molecular level should allow us to intervene when these processes fail and result in cancer and other virus-associated diseases.
Recent Publications:
Verma, D and Swaminathan, S. Epstein-Barr virus SM protein functions as an alternative splicing factor J Virol. 2008 Jul;82(14):7180-8. Epub 2008 May 7. http://jvi.asm.org/cgi/content/abstract/82/14/7180
Swaminathan, S. Noncoding. RNAs produced by oncogenic human herpesviruses. J Cell Physiol. 2008 Aug;216(2):321-6. http://www3.interscience.wiley.com/cgi-bin/fulltext/119141510/HTMLSTART
Nekorchuk M, Han Z, Hsieh TT, Swaminathan S. Kaposi's sarcoma-associated herpesvirus ORF57 protein enhances mRNA accumulation independently of effects on nuclear RNA export. J Virol. 2007 Sep;81(18):9990-8. http://jvi.asm.org/cgi/content/full/81/18/9990?view=long&pmid=17609285
Han Z, Swaminathan S. Kaposi's sarcoma-associated herpesvirus lytic gene ORF57 is essential for infectious virion production. J Virol. 2006 Jun;80(11):5251-60.
Swaminathan S. Post-transcriptional gene regulation by gamma herpesviruses. J Cell Biochem. 2005 Jul 1;95(4):698-711.
Nicewonger J, Suck G, Bloch D, Swaminathan S. Epstein-Barr virus (EBV) SM protein induces and recruits cellular Sp110b to stabilize mRNAs and enhance EBV lytic gene expression. J Virol. 2004 Sep;78(17):9412-22.
Ruvolo V, Sun L, Howard K, Sung S, Delecluse H-J, Hammerschmidt W, Swaminathan S. Functional analysis of Epstein-Barr virus SM protein: identification of amino acids essential for structure, trans-activation, splicing inhibition and virion production. J. Virol. 2004,78(1): 340-352.
Ruvolo V, Navarro L, Sample C, David M, Swaminathan S. The Epstein-Barr Virus SM protein activates STAT1 and induces interferon stimulated gene expression. J. Virol. 2003, 77(6):3690-701.
Gupta, AK, Ruvolo, V, Patterson, C, Swaminathan, S. The HHV8 homolog of Epstein Barr Virus SM protein (KS-SM) is a post-transcriptional activator of gene expression. J. Virol. 2000, 74:1038-44.
Boyle, S, Ruvolo, V, Gupta, AK, Swaminathan, S. Association with the cellular export receptor CRM1 mediates function and intracellular localization of the EBV SM protein, a regulator of gene expression. J. Virol. 1999, 73:6872-6881.
Ruvolo, V, Wang, E, Boyle, S, Swaminathan, S. The Epstein-Barr virus nuclear protein SM is both a post-transcriptional inhibitor and activator of gene expression. Proc. Natl. Acad. Sci. 1998; 95:8852-8857.
