Last Updated: 4/20/2007

Joseph S. Pagano, M.D. Professor, Director Emeritus Virology

Research Interests
The Epstein-Barr virus (EBV) is associated with malignancies of lymphocytic and epithelial origin. EBV produces different infection states, cytolytic and latent, as well as cell immortalization, all of which are captured in cell lines, making them accessible to mechanistic studies. Currently, our research deals with viral latency, the ubiquitin-proteasome system in cell signaling, interferon regulatory factors (IRFs), invasion and metastasis, and antiviral drugs.

In EBV's cytolytic infection cycle we are focusing on two EBV gene products. One encodes EBV's sole protein kinase which phosphorylates other viral products, including the EBV DNA processivity factor used in viral replication and viral maturation proteins involved in egress of viral nucleocapids from the nucleus. We are also studying a recently discovered EBV-encoded deubiquitinating enzyme and its role in the viral cytolytic cycle.

In latent infection we study how the cell cycle serves as a global regulator of viral latent gene expression through its effects on the major nuclear proteins, EBNA1 and EBNA2. We also study mechanisms of cell immortalization and oncogenesis through EBV's ability to stabilize and activate b-catenin via the ubiquitin system. IRF7 was discovered in this laboratory, and how EBV is able to mount and evade immune responses through the ability of EBV LMP1 to induce and activate IRF7, now recognized as the master regulator of type I interferon responses, remains a principal focus. Finally we hold that EBV, in addition to being the etiologic agent for several malignancies, may also serve to promote tumor progression by the ability of its major oncoprotein, LMP1, to induce invasion, metastasis and angiogenic factors. Common to these areas is our emphasis on the role of tumor viruses in the ubiquitin-proteasomal system.

All trainees are encouraged to broaden their experience by also participating in the well known UNC-LCCC Postdoctoral Training Program, to assist in progressing toward their career goals. Fellows will also present their work in progress at one of the weekly meetings of the extended Virology Faculty at UNC.

Recent Accomplishments and Honors
The most important recent discoveries from our laboratory are that:

1. LMP1, the principal oncoprotein of EBV, activates IRF7 through a RIP- and TRAF6-dependent ubiquitination pathway.


2. A tumor virus, EBV, can activate the β-catenin signaling pathway in human lymphocytes.


3. Activation of the β-catenin pathway is through a novel mechanism, namely, the induction or activation of one or more deubiquitinating enzymes.


4. IRF-7 has oncogenic properties that may potentiate those of LMP-1, the principal EBV oncoprotein, and it is overexpressed in CNS lymphomas.


5. Among the invasion and metastasis factors that we have discovered are induced by EBV — MMP-9, COX-2, VEGF, FGF-2 — the most recent is HIF-1α. The EBV oncoprotein LMP-1 is again the first known tumor virus protein shown to induce HIF-1α, the sole transcription factor that mediates all known cellular responses to low oxygen tension.

Publications
Recent Selected Publications:

1. Yue, W., Liu, R., Pagano, JS., Shackelford, J.
   Ubiquitin C-terminal hydrolase L1 stabilizes and activates Beta-catenin through deubiquitination. Submitted
   


2. Ceccarelli S, Wakisaka N, Pagano JS, Torrisi, MR
   Epstein-Barr virus latent membrane protein 1 promotes concentration in multivesicular bodies of fibroblast growth factor 2 and its release through exosomes.
   International Journal of Cancer. 2007. (In press)
    


3. Pagano JS.
   Is Epstein-Barr virus transmitted sexually?
   J. Infect. Dis. 2007. 195(4):469-70. Epub 2007 Jan 10.
   Full Text (HTML)|Reprint (PDF)
    


4. Gershburg, E., Raffa, S., Torrisi, M. R. and J. S. Pagano
   Epstein-Barr virus-encoded protein kinase (BGLF4) is invovled in production of infectious virus.
   Journal of Virology. 2007. March 14. Epub ahead of print



5. Huye, L.*, Ning, S.*, Kelliher, M., Pagano, J. IRF7 is activated by a viral oncoprotein through RIP-dependent ubiquitination.
   Molecular and Cellular Biology. 2007. 27(8): 2910-2918.
   * Contributed equally to the work.
   Abstract|Full Text (HTML)|Reprint (PDF)



6. Horikawa T, Yang J, Kondo S, Yoshizaki T, Joab I, Furukawa M, Pagano JS.
   Twist and Epithelial-Mesenchymal Transition are Induced by the Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 and are Associated with Metastatic Nasopharyngeal Carcinoma.
   Cancer Res 2007. 67(5): 1970-1978
   Abstract|Full Text (HTML)|Reprint (PDF)



7. Kondo S, Yoshizaki T, Wakisaka N, Horokawa T, Murono S, Jang KL, Joab I, Pagano JS.
   MUC1 induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of Cell-Matrix Interaction and cellular Invasiveness via STAT Signaling.
   J. Virol. 2007. 81(4): 1554-1562
   Abstract|Full Text (HTML)|Reprint (PDF)



8. Kondo S, Seo SY, Yoshizaki T, Wakisaka N, Furukawa M, Joab I, Jang KL, Pagano JS.
   EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells.
   Cancer Res. 2006 Oct 15;66(20):9870-7.
   Abstract|Reprint (PDF)
   PMID: 17047048
   


9. Yue, W., Shackelford, J., Pagano, JS.
   cdc2/cyclin B1-dependent phosphorylation of EBNA2 at Ser243 regulates its function in mitosis.
   J Virol. 2006 Feb; 80(4):2045-50.
   Abstract|Full Text (HTML)|Reprint (PDF)
   PMCID:1367142



10. Jang, KL.*, Shackelford, J.*, Seo SY, Pagano, JS.
    Up-regulation of Beta-catenin by a viral oncogene correlates with inhibition of Siah-1 ubiquitin ligase in B-lymphoma cells.
    Proc Natl Acad Sci U S A. 2005, 102(51):18431-6.
    *Contributed equally to this work
    Abstract|Full Text (HTML)|Reprint (PDF)
    PMCID:1317901
    


11. Yue, W., Gershburg, E., Pagano, J.S.
    Epstein-Barr Virus protein kinase phosphorylates EBNA2 and suppresses EBNA2 transactivation of the LMP1 promoter.
    J. Virol., 2005. 79(9): 5880-5885.
    Abstract|Full Text (HTML)|Reprint (PDF)
    


12. Shackelford J., Pagano JS.
    Targeting of host-cell ubiquitin pathways by viruses.
    In Essays in Biochemistry, 2005 41: 139-156. Portland Press Ltd. London, UK.
    Abstract
    


13. Wakisaka, N., Yoshizaki, T., Murono, S., Furukawa, M., Raab-Traub, N., Pagano, J.S.
    Ribonucleotide reductase inhibitors enhance cidofovir-induced apoptosis in EBV-positive nasopharyngeal carcinoma xenografts.
    Int. J. Cancer. 2005. 116: 640-645
    Abstract|Full Text (HTML)|Reprint (PDF)



14. Kondo S, Wakisaka N, Schell MJ, Horikawa T, Sheen TS, Sato H, Furukawa M, Pagano JS, Yoshizaki T.
    Epstein-Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: Enhanced susceptibility to nasopharyngeal carcinoma.
    Int. J. Cancer, 2005. 115(3):368-376
    Abstract|Full Text (HTML)|Reprint (PDF)



15. Yoshizaki, T., Wakisaka, N. and Pagano, J.S.
    Epstein-Barr virus invasion and metastasis.
    2005. Chapter 12. in: Epstein-Barr virus. Ed. by E. Robertson. Caister Academic, Norfolk, England. 171-196.
    Abstract|Full Text (HTML)|Reprint (PDF)
    


16. Pagano, J. S.
    Infectious Mononucleosis.
    In: PIER [Online database], 2005. Philadephia. American College of Physicians.
    Full Text [login required]



17. Qing,J., C. Liu, L. Choy, RY Wu, J.S. Pagano, R. Derynck.
    TGF-b/Smad3 signaling regulates IRF-7 function and transcriptional activation of the interferon-beta promoter.
    Mol. Cell Biol. 24:3:1411-1425,2004.
    Abstract|Full Text (HTML)|Reprint (PDF)
    PMID: 14729983






Click here for a list of Publications on PubMed

E-mail: joseph_pagano@med.unc.edu
Telephone: (919) 966-8644
FAX: (919) 966-9673
Address: 32-000 Lineberger, CB# 7295 Chapel Hill, NC
URL: paganolab.net


Click here to update this profile