Joseph S. Pagano

pagano joseph

 

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 the different states accessible to mechanistic studies. Recently Dr. Pagano's lab has access to a humanized mouse model (see Lishan Su, http://unclineberger.org) for EBV infection and transformation studies. Currently their research deals with viral latency, functions of the EBV protein kinase and deubiquitinating enzymes in EBV systems, interferon regulatory factors (IRFs), invasion and metastasis induced by the EBV oncoprotein LMP1, 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 at least 20 EBV proteins, including the EBV DNA polymerase processivity factor used in viral replication, viral maturation proteins involved in egress of viral nucleocapids from the nucleus, and the R1 subunit of the EBV ribonucleotide reductase (RR). The other gene encodes the EBV deubiquitinating enzyme (DUB), which down-regulates function of the EBV RR, the first target identified for herpesvirus DUBs.

They also study mechanisms of cell immortalization and oncogenesis through EBV's ability to stabilize and activate β-catenin via the ubiquitin system with the focus on the cellular deubiquitinating enzyme, UCH L1. This DUB is induced by the master transcriptional transactivator, EBNA2, in EBV-transformed cells. Recently we discovered 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. How EBV is able to mount and evade IRF7-mediated immune responses, and the ability of EBV LMP1 to induce and activate IRF7, now recognized as the master regulator of type I interferon responses, through ubiquitination remain principal focuses.

Finally they hold that EBV, in addition to being an etiologic agent for its associated malignancies, may also serve to promote tumor progression. EBV’s major oncoprotein LMP1 can induce epithelial-mesenchymal transition (EMT) and promote cell migration through up-regulation of invasion, metastasis and angiogenic factors in NPC, as shown recently with Twist and Snail transcription factors and through phosphorylation of the ERM family member, Ezrin.


 

 

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