TitleMolecular and pharmacological study of transcription factor Nrf2
NameLin, Wen (author), Kong, Ah-Ng (chair), Minko, Tamara (internal member), Suh, Nanjoo (internal member), Heimbach, Tycho (outside member), Huang, Mou-Tuan (outside member), Rutgers University, Graduate School - New Brunswick,
DescriptionNuclear 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.
NoteIncludes bibliographical references (p. 139-149)
Noteby Wen Lin
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
RightsThe author owns the copyright to this work.