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dc.contributor.authorLi, Yongan
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 57-04, Section: B, page: 2356.;Advisors: Marshall S. Horwitz.
dc.description.abstractTNF-{dollar}\alpha{dollar} is an important inflammatory cytokine which affects numerous immune responses and cellular processes. However, its signal transduction pathways are poorly understood. Adenoviruses (Ad) encode four proteins that can inhibit TNF-{dollar}\alpha{dollar} cytolysis by unknown mechanisms; these include the E1B-19KDa protein, which is a homologue of the Bcl-2 protein, the E3-14.7KDa protein (called E3-14.7K) and the E3-14.5KDa/10.4KDa heterodimer. The goal of our current studies is to identify and characterize the cellular targets which interact with E3-14.7K and to further our understanding of the TNF-{dollar}\alpha{dollar} signaling pathways.;By the use of the yeast two-hybrid system, four unique clones that code for {dollar}\underline{lcub}14{rcub}{dollar}.7k-interacting proteins or FIPs have been identified. We showed that FIPs interact in vitro and colocalize in vivo with E3-14.7K. Each of the four FIPs was able to cause cytolysis when overexpressed in human cells. TNF-{dollar}\alpha{dollar} induced rapid but transient phosphorylation and association of FIP-1 with other cellular proteins. The stable expression of each antisense FIP message could partially protect cells from TNF-{dollar}\alpha{dollar} cytolysis. These results suggest that FIPs are directly involved in TNF-{dollar}\alpha{dollar} signal pathways.;All four FIPs are novel proteins and are expressed in all major human tissues assayed. FIP-1 has regions of homology with other Ras-related small GTP binding proteins but has a unique carboxyl terminus. Mutagenesis analysis has shown that the GTP-binding domain of FIP-1 is indispensable for its interaction with E3-14.7K. FIP-1 is very similar to two proteins: (1) an S. cerevisiae GTP-binding protein that presumably has a role in phosphate transport and (2) a C. elegans protein of unknown function. FIP-1 also has sequence homology to two prokaryotic metalloproteases. FIP-2 and FIP-3 are similar proteins containing leucine-zipper domains. The domains important for interaction with E3-14.7K are mapped. Our results here demonstrate that E3-14.7K interacts with several novel cellular proteins which are presumably the direct signal transducers of TNF-{dollar}\alpha{dollar}. By interacting with these proteins, E3-14.7K is able to block TNF-{dollar}\alpha{dollar}-induced cytolysis. Our results also suggest that E3-14.7K is acting at steps or pathways of TNF-{dollar}\alpha{dollar} cytolysis different from the ones affected by E1B-19K or Bcl-2 since none of the FIPs interact with either Bcl-2 or ElB-19K.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.subjectCellular biology.
dc.titleIdentification and characterization of cellular proteins which interact with adenovirus E3-14.7KDa protein, an antagonist of TNF-alpha

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