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Dissertation/Thesis Abstract

An analysis of latent membrane protein-1 signaling complexes and their contribution to Epstein-Barr virus infection
by Takeshita, Ryan Akira, Ph.D., University of Colorado at Boulder, 2011, 222; 3453795
Abstract (Summary)

In immunocompromised individuals, B cells infected with Epstein-Barr virus often display tumorigenic growth. One of the viral oncoproteins that contributes to this transformation is the latent membrane protein-1 (LMP-1), which constitutively mimics the signaling of ligand-dependent CD40, a tumor necrosis factor receptor. The experiments described in this dissertation were designed to elucidate the molecular mechanisms that underlie LMP-1's signaling potential. We investigated the relationships between LMP-1's subcellular localization, homo-oligomerization, comigration with detergent-resistant membranes, and its signaling outputs in order to bridge some of the gaps standing in the way of a unified theory of LMP-1 function. The data presented here are consistent with a working model where LMP-1's transmembrane domain drives local homo-oligomerization of small complexes, which in turn are assembled into larger megameric complexes, each with some capacity to perform LMP-1 signaling events. These megameric complexes, or LMP-1-enriched domains (LEDs), create an environment that is either particularly resistant to cholesterol-extraction by methyl-β-cyclodextrin or that has cholesterol-independent DRM-like properties. Upon saturation of this pathway, nascent LMP-1 populates a new subset of juxtanuclear membrane compartments. LED formation is important for proper NFκB signaling and therefore is a promising target for the design of therapeutics against LMP-1-dependent EBV-associated diseases and malignancies.

Indexing (document details)
Advisor: Martin, Jennifer M.
Commitee: Garcea, Robert, Olwin, Bradley, Palmer, Amy, Stowell, Michael
School: University of Colorado at Boulder
Department: Molecular, Cellular and Developmental Biology
School Location: United States -- Colorado
Source: DAI-B 72/07, Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Virology
Keywords: Epstein-Barr virus, Homo-oligomerization, Latent membrane protein-1, Lipid rafts, Subcellular localization
Publication Number: 3453795
ISBN: 978-1-124-62157-9
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