Characterization and sequence specificity of antioxidant/electrophile response element binding proteins in vascular smooth muscle cells /
Exposure to environmental chemicals such as polycyclic aromatic hydrocarbons (PAHs), has long been implicated as a factor leading to the onset of atherosclerosis. Benzo[a]pyrene (BaP), a prototypical PAH and persistent environmental contaminant, activates intracellular mechanisms involved in the de...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
2002.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=764789791&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | Exposure to environmental chemicals such as polycyclic aromatic hydrocarbons (PAHs), has long been implicated as a factor leading to the onset of atherosclerosis. Benzo[a]pyrene (BaP), a prototypical PAH and persistent environmental contaminant, activates intracellular mechanisms involved in the deregulation of proliferation of vascular smooth muscle cells (vSMCs) in the arterial wall, leading to the formation of atherosclerotic lesions. BaP is metabolized by cytochrome P450 to reactive metabolites, free radicals, peroxides and quinones that upset the redox balance within the cell, causing alterations in signaling pathways, protein function, and gene expression. c-Ha-ras, a constitutive growth regulatory gene, is transcriptionally activated in vSMCs in response to both BaP and oxidant challenge. It is hypothesized that this trans-activation involves protein complex assembly on an antioxidant/electrophile response element (ARE/EpRE) located in the 5' regulatory region of this gene. Metabolites and reactive oxygen species (ROS) generated through BaP metabolism may activate cellular proteins to bind ARE/EpRE and deregulate transcription of c-Ha-ras. The proteins that recognize the ARE/EpRE in c-Ha-ras, and the mechanism by which they are activated to bind, are not currently known. Research detailed in this proposal examines the hypothesis that a complex of proteins activated by chemical and oxidative challenge to bind an ARE/EpRE in the upstream promoter region of c-Ha-ras, transactivates this gene. The specific nucleotide sequence comprising this response element, as well as flanking sequences, are likely to influence complex recruitment and protein complex stabilization. Furthermore, the identity of regulatory transcription factors may be similar to those already identified in other promoters, while others may prove to be novel. To examine these hypotheses, the proposed studies are designed to: 1) determine the functional properties of ARE/EpRE binding proteins in c-Ha-ras; 2) identify candidate proteins that bind to ARE/EpRE; and 3) determine DNA sequences in and around the specific response element that influence protein complex assembly. Ultimately, this work will provide an interpretation of a key mechanism by which vSMCs are phenotypically altered by toxic challenge to migrate, proliferate and form atherosclerotic lesions within the arterial wall. |
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| Item Description: | Vita. "Major Subject: Toxicology". |
| Physical Description: | xvi, 213 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 165-212). |