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Title: Redox regulation of ne-kB activation by hydrogen peroxide and effects on gene expression
Author: Marques, Virgínia Mylena de Oliveira, 1980-
Advisor: Antunes, Fernando José Nunes, 1969-
Cyrne, Maria Luísa Santos de Sousa, 1954-
Keywords: Peróxido de hidrogénio
Reação de oxidação-redução
Expressão genética
Teses de doutoramento
Defense Date: 2009
Abstract: Evidences suggest that hydrogen peroxide (H2O2) is implicated in the regulation of the transcription factor NF-κB. However, no consensus exists regarding the role played by H2O2 since both inhibitory and stimulatory effects have been reported. It was hypothesized that these contradictory data are due to the methodology used to expose cells to H2O2. Usually, H2O2 is added at the beginning of the experiment bolus addition in high concentrations of H2O2 needed because of its rapid consumption by cells. Therefore the real [H2O2] that is exerting the effects is not known and the high initial dose masks a signaling role for H2O2 and often causes elevated oxidative damages. In this work a different methodology was used the steady-state (s.s.) titration whereby the use of glucose oxidase allows cells to be exposed to constant, lower and nearer to the physiological H2O2 concentrations. NF-κB is a key regulator of the inflammatory process, innate and adaptive immunity. In this work [H2O2] in s.s., similar to those generated at inflammation sites, modulated positively NF-κB activation induced by the pro-inflammatory cytokine TNF-α. H2O2 increased the degradation of IκB-α, the major inhibitor of NF-κB and, in MCF-7 cells, this caused higher levels of nuclear NF-κB-containing p65 and c-Rel proteins. In HeLa cells, c-Rel proteins were retained in the cytosol probably by IκB-ε. The higher NF-κB levels in the nucleus induced by H2O2 and TNF-α together were predicted to be important for the expression genes with low/medium-affinity κB sites, which is in accordance with the selective gene expression observed. In MCF-7 and HeLa cells treated with TNF-α, H2O2 up-regulated both pro- and anti-inflammatory NF-κB-dependent genes. Therefore, it was proposed a dual regulatory role for H2O2 in inflammation by simultaneously exacerbating inflammation through higher levels of pro-inflammatory mediators and by attenuating possible adverse effects through induction of anti-inflammatory genes expression.
Description: Tese de doutoramento em Bioquímica (Regulação Bioquímica), apresentada à Universidade de Lisboa através da Faculdade de Ciências, 2009
Appears in Collections:FC - Teses de Doutoramento

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