Joseph Pagano

MD, School of Medicine, Department of Microbiology and Immunology, UNC-Chapel Hill, Cancer Research, Infectious Diseases, Virology

Joseph Pagano

MD
Department of Microbiology and Immunology
School of Medicine
UNC-Chapel Hill
Cancer Research, Infectious Diseases, Virology 

32-000 Lineberger
966-5907

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Clinical profile

Area of interest

The Epstein-Barr Virus (EBV) is associated with and causes malignancies of lymphocytic and epithelial origin. EBV produces different infection states, cytolytic and latent, as well as immortalization of human cells, all of which are captured in cell lines, making the different states accessible to mechanistic studies. Recently we have access to a humanized mouse model (see Lishan Su) in which human B-cell lymphomas can be generated. Our research now includes deubiquitinating enzymes in EBV systems, viral latency, functions of the EBV protein kinase and antiviral drugs and regulation by EBV’s principal oncoprotein LMP1, of invasion and metastasis factors.

In EBV’s cytolytic infection cycle our focus is on two EBV gene products. The first gene encodes the EBV deubiquitinating enzyme (DUB), which down-regulates function of the EBV ribonucleotide reductase (RR), the first target identified for herpesvirus DUBs. The other encodes EBV’s sole protein kinase, which phosphorylates at least 20 EBV proteins, including the EBV DNA polymerase processivity factor used in viral replication.

We focus on mechanisms of cell immortalization and oncogenesis including EBV’s ability to stabilize and activate β-cartenin via the ubiquitin system through action of the cellular deubiquitinating enzyme (DUB), UCH L1. This DUB is induced by the EBV master transcriptional transactivator, EBNA2, in virus-transformed cells. We have found that UCH L1 is expressed in association with the mitotic spindle and regulates microtubule dynamics in diverse transformed cells.

IRF7 was discovered in this laboratory. We subsequently showed how EBV is able to mount and evade IRF7-mediated immune responses, as well as the ability of EBV LMP1 to induce and activate IRF7 through ubiquitination. IRF7 is considered the master regulator of type I interferon responses.

EBV in addition to being etiologic agent for several of its associated malignancies can also serve to promote tumor progression. EBV’s major oncoprotein LMP1 can induce epithelial-mesenchymal transition (EMT) through up-regulation of transcription factors such as Twist and Snail that are activated in nasopharyngeal carcinoma (NPC) in invasion and metastasis, which remains the frontier in cancer research.

Finally, we have proposed that the exosome-mediated transfer to non-EBV infected cells of active transcription factors promotes the process of local invasion of NPC by affecting not only tumor cells themselves, but also components of the stromal tissue. In a recent paper we demonstrate that pro-metastatic transcription factors such as HIF-1α secure immediate changes in gene expression in uninfected recipient cells through exosome uptake. Hence exosomes from EBV-positive metastatic NPCs offer not only new opportunities for biomarker analysis, but may present targets for therapeutic intervention. 

Training

Trainees are encouraged to attend LCCC seminars, symposiums, and participate in events sponsored by the UNC-LCCC Postdoctoral Training Program, now in its 41st year, to promote their career goals.  I also sponsor selected Fellows for support by this National Cancer Institute-funded training grant.  Fellows in my laboratory also present work in progress at the weekly meetings of the Virology Faculty at UNC.

Awards and Honors

Recent discoveries:

  • The neuronal protein UCH L1 is aberrantly expressed in a variety of carcinomas and lymphomas.  A fundamental function for this ubiquitin-editing enzyme:  its deubiquitinating and ubiquitin ligase activities are associated with tubulin throughout mitosis and affect its polymerization.
  • A tumor virus, EBV, can activate the β-catenin signaling pathway in human lymphocytes through a novel mechanism, induction of the deubiquitinating enzyme UCH L1.
  • LMP1, the principal oncoprotein of EBV, activates IRF7 through a RIP- and TRAF6=dependent ubiquitination pathway.
  • IRF-7 has oncogenic properties that may potentiate those of LMP-1.
  • Twist, a transcriptional factor essential for breast cancer metastasis and epithelial-mesenchymal transition, is co-expressed with LMP1 in nasopharyngeal carcinoma tissues.
  • Phosphorylation of Ezrin, a member of the ERM family that links plasma membrane and the actin cytoskeleton and drives cell immigration, is induced by LMP1 and detected in nasopharyngeal carcinoma tissues.
  • The selective antiviral drug Maribavir is activated by the EBV protein kinase, and in contrast to Acyclovir inhibits not only viral replication but viral transcription.
  • EBV’s ribonucleotide reductase is deactivated by EBV’s deubiquitinating enzyme (DUB) and retards cell cycle progression.  This is the first target discovered for the EBV DUB.
  • EBV’s DUB can disrupt the process of DNA repair, translesion synthesis  (TLS) by deubiquitinating mono-ubiquitinated PCNA the cellular DNA processivity factor.  This is the first cellular target identified for the enzyme.

Honors: 

1998 - PresentMember, National Academy of Medicine (formerly Institute of Medicine)
2012 Honorary Professor, Kanazawa University, Kanazawa, Japan
2012 – 2014

Member, Board of Directors, Executive Committee, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

2012 Fellow, American Academy of Microbiology
2008 – 2012 Member, Science Advisory Board, US Food & Drug Administration
2009

American Representative, Installation of Vice-Chancellor, Kanazawa University

2004

Fellow, American Association for the Advancement of Science

Link to Publications on Reach NC site

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