Molecular and pharmacological study of transcription factor Nrf2

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Molecular and pharmacological study of transcription factor Nrf2

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Descriptive

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Text

TitleInfo (ID = T-1)

Title

Molecular and pharmacological study of transcription factor Nrf2

SubTitle

a master regulator of cellular antioxidant defense enzymes

PartName

PartNumber

NonSort

Identifier

ETD_1463

Identifier (type = hdl)

http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051045

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eng

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theses

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Topic

Pharmaceutical Science

Subject (ID = SBJ-2); (authority = ETD-LCSH)

Topic

Antioxidants--Physiological effect

Subject (ID = SBJ-3); (authority = ETD-LCSH)

Topic

Enzyme activation

Subject (ID = SBJ-4); (authority = ETD-LCSH)

Topic

Transcription factors

Abstract

Nuclear factor E2-related factor 2 (Nrf2) is a key regulator of ARE-mediated gene expression of Phase II detoxifying enzymes and antioxidant enzymes. In the proposed study, we tested whether nuclear receptor-associated coactivator-3 (RAC3) could participate in the stimulation of transactivation activity of Gal4-Nrf 2 (1-370) with other coactivators. We showed for the first time that the p160 coactivator RAC3 could stimulate the transactivation activity of Gal4-Nrf 2 (1-370) and this could be further enhanced by the coregulators CBP, p/CAF, CARM-1, and PRMT1. Besides, we found that regulation of Nrf2-dependent ARE-driven gene expression by small Mafs protein is dependent on dosage and the ratio of Maf to Nrf2. On the other hand, ERK2 significantly enhanced the expression of ARE-driven luciferase. ERK2 and MafG synergistically upregulated the Nrf2-activated ARE-driven luciferase expression. Nrf2 was identified as a direct substrate of ERK2 both in vivo as well as in vitro for the first time. The phosphorylation of Nrf2 by ERK2 increased its heterodimerization with small Maf proteins. To extrapolate the implication of Nrf2 in inflammation, we compared the anti-inflammatory effect of sulforaphane on LPS-stimulated inflammation in primary peritoneal macrophages derived from Nrf2 (+/+) and Nrf2 mice. The anti-inflammatory effect was attenuated in Nrf2 (-/-) primary peritoneal macrophages. We concluded that sulforaphane exerts its anti-inflammatory activity mainly via activation of Nrf2 in mouse peritoneal macrophages. To better facilitate application of sulforaphane in therapeutics, the pharmacokinetics characterization was investigated in rats. Toxicogenomics study of peroxisome proliferator-activated receptor γ agonist (PPARγ) troglitazone (TGZ) in mouse liver as well as to identify TGZ modulated Nuclear Factor-E2-related factor 2 (Nrf2)--dependent genes was performed. Utilization of animal model of cellular defense deficiency identified Nrf2-dependent genes in response to TGZ and reveals the role of Nrf2 molecule in toxicity caused by TGZ.

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electronic resource

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xiii, 151 p. : ill.

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Ph.D.

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Includes bibliographical references (p. 139-149)

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by Wen Lin

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Lin

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Wen

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Wen Lin

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Kong

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Ah-Ng

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Ah-Ng Kong

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Minko

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Tamara

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Tamara Minko

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Suh

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Nanjoo

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Nanjoo Suh

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Heimbach

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Tycho

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Tycho Heimbach

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Huang

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Mou-Tuan

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Mou-Tuan Huang

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Rutgers University

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degree grantor

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Graduate School - New Brunswick

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school

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2009

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2009-01

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NjNbRU

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Rutgers University Electronic Theses and Dissertations

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ETD

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Graduate School - New Brunswick Electronic Theses and Dissertations

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rucore19991600001

Identifier (type = doi)

doi:10.7282/T34X5819

Genre (authority = ExL-Esploro)

ETD doctoral

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The author owns the copyright to this work.

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Non-exclusive ETD license

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Author Agreement License

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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.

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application/pdf

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1136640

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