Modulation of Signal Transduction and Transformation by Kaposi’s Sarcoma-Associated Herpesvirus Public Deposited

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  • March 19, 2019
Creator
  • Anders, Penny
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Kaposi’s sarcoma associated-herpesvirus (KSHV) is a double-strand DNA gamma herpesvirus that establishes lifelong latent infection in the human host. KSHV infection is associated with several cancers including the endothelial cell cancer, Kaposi’s sarcoma (KS); and two B-cell lymphomas, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. This dissertation focuses on the importance of cellular signal transduction pathways in KSHV-associated cancers and focuses on two KSHV viral proteins, K1 and vPK, that modulate these signaling pathways. KSHV encodes over 100 genes including many proteins that alter signaling pathways to create a cellular milieu that promotes survival of the virally infected cell. The PI3K and MAPK signaling pathways are aberrantly active in PEL and other non- Hodgkin lymphomas (NHL), and are important for PEL survival. Because there is always a need for new effective therapies to treat NHL, which includes KSHV-infected PEL, we sought to evaluate the effectiveness of dual inhibition of the PI3K and MAPK signaling pathways in killing NHL cells. We concluded that dual inhibition of both pathways was no more effective at reducing cell viability and tumor burden in vivo than inhibition of the PI3K pathway alone. Some viral proteins modulate host cellular proteins and thereby promote KSHV pathology. The KSHV K1 viral protein is thought to be a major contributor to KSHV-induced oncogenesis since the expression of K1 has been shown to lead to transformation in vitro and to tumor development in vivo. We identified AMPKγ1 as a K1-associating protein, and the K1 N-terminus is important for association with AMPKγ1. AMPK is a metabolic regulator that responds to many types of cellular stress by regulating pathways to maintain energy homeostasis. We found that K1 expression gives cells a survival advantage when cells are stressed by serum starvation or when AMPK is inhibited, and that this survival advantage is dependent on K1’s association with AMPK. AMPK activity is also increased in K1-expressing cells following exposure to metabolic stress. Unlike K1, which is unique to KSHV, vPK (ORF36) is a viral serine/threonine kinase that is conserved among herpesviruses, underscoring the importance of this kinase in herpesvirus infection and KSHV biology. Our lab has found that vPK expression facilitates cellular transformation in vitro and that vPK phosphorylates ribosomal protein S6, a protein that is typically phosphorylated by S6 kinase and involved in protein synthesis. Thus far, our understanding of vPK function and its impact on the host has been based on data obtained from in vitro culture models. We sought to add novel insight into the function of vPK by evaluating the phenotype of vPK in vivo. We found that naïve vPK transgenic mice have an activated immune system that is similar to immunized wild-type mice. Moreover, aged-vPK mice are more prone to lymphoma development than wild-type mice.
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Rights statement
  • In Copyright
Advisor
  • Dittmer, Dirk
  • Raab-Traub, Nancy
  • Damania, Blossom
  • Moorman, Nathaniel
  • Johnson, Gary
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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