Transcriptional regulation of the human immunodeficiency virus by protein phosphatase 2A.
dc.contributor.author | Faulkner, Neil Esantis | |
dc.contributor.advisor | Markovitz, David M. | |
dc.date.accessioned | 2016-08-30T15:16:50Z | |
dc.date.available | 2016-08-30T15:16:50Z | |
dc.date.issued | 2003 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3079440 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/123379 | |
dc.description.abstract | Regulation of HIV gene transcription is mediated by a number of response elements that serve to integrate the signaling pathways initiated by a variety of cell stimulatory agents and culminating at the level of the HIV promoter/enhancer. Although much is known about the kinases that mediate many of these signaling pathways, only recently have the phosphatases that negatively or positively regulate these cascades garnered much attention. Protein phosphatase 2A (PP2A), a ubiquitous, multimeric enzyme responsible for the majority of intracellular serine/threonine phosphatase activity has been implicated in the regulation of HIV transactivation. This dissertation examines the effects of ectopic expression of the catalytic domain of PP2A (PP2Ac) on the activities of both the HIV-1 and HIV-2 promoter. We demonstrate that ectopic PP2Ac upregulates the basal activity of the HIV-1 and HI V-2 promoters in a dose-dependent manner in U937 monocytic cells. We have identified three elements (pets, Sp1, and PuB2) in the HIV-2 promoter and two (Sp1 and TATA) in the HIV-1 promoter that mediate the response to PP2Ac. The pets site is found only in HIV-2 strains but not HIV-1. Our laboratory identified the oncoprotein DEK as one of the nuclear factors capable of binding to the pets site in unstimulated cells. We show that intracellular DEK levels and DEK binding to the HIV-2 pets site are greatly diminished with TPA treatment of U937 cells, leading to a faster migrating complex in gel shift assays. These actions of TPA on DEK binding can be mimicked with phosphatase treatment of nuclear extracts from unstimulated cells or blocked with the PP2A specific inhibitor okadaic acid. Finally, we are able to show that ectopic PP2A can increase HIV-1 replication in TPA-stimulated U937 cells in a dose dependent manner and that HIV-1 replication is inhibited by okadaic acid. Taken together, these findings implicate PP2A as an activator of HIV transcription and replication and a regulator of DEK DNA-binding. Most importantly, they extend our understanding of HIV pathogenesis and suggest alternative therapeutic approaches for the treatment of HIV/AIDS. | |
dc.format.extent | 117 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Dek Oncoproteins | |
dc.subject | Hiv | |
dc.subject | Human | |
dc.subject | Immune Deficiency | |
dc.subject | Immunodeficiency | |
dc.subject | Protein Phosphatase 2a | |
dc.subject | Regulation | |
dc.subject | Transcriptional | |
dc.subject | Virus | |
dc.title | Transcriptional regulation of the human immunodeficiency virus by protein phosphatase 2A. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Biological Sciences | |
dc.description.thesisdegreediscipline | Cellular biology | |
dc.description.thesisdegreediscipline | Molecular biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/123379/2/3079440.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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