Redox-Responsive Transcription Factors

Oxygen sensors of the peripheral and central nervous systems 

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Haddad JJ. 2002. Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology. Respir Res 3 26. 

Saito T, RW Deskin, A Casola, H Haeberle, B Olszewska, PB Ernst, R Alam, PL Ogra, R Garofalo. 1997. Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells. J Infect Dis 175 497. Roebuck KA, LR Carpenter, V Lakshminarayanan, SM Page, JN Moy, LL Thomas. 1999. Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kappaB. J Leukoc Biol 65 291. 

It now seems that an overdose of paracetamol causes a massive chemical stress, which causes an immediate adaptive defense response in the liver cell, which senses danger via redox-sensitive transcription factors. A number of mechanisms are involved, including the release, as a result of the stress, of a transcription factor Nrf-2 from its binding with Keap 1, a cytoplasmic inhibitor. Nrf-2 translocates to the nucleus and with other activators binds to an antioxidant-response element. This leads to transcription of a number of genes, so producing a... 

Moreover GSH concentration indirectly controls a host of redox-sensitive transcription factors such as NF-kB and AP-1, modulates the genes for pro-inflammatory mediators as well as protective antioxidant genes such as y-GCS, Mn-superoxide dismutase, and heme oxygenase-1. Also TNF-a, p38 MAP kinase activation and p38 MAP kinase-mediated RANTES (regulated upon activation, normal T-cells expressed and secreted ) production is redox regulated [24]. The role of RANTES in the inflammatory and allergic response has been recently elucidated [25], indicating a role of intracellular GSH also in this particular field of inflammation. 

The oxidation of thiol groups disrupts redox balance (deflned later in this chapter), which can set into motion a cascade of events, such as apoptosis, oxidant production, and increased activity of redox-regulated transcription factors (e.g., nuclear factor kappa beta [NF-kB]). The occurrence of OS is not isolated to the vesicant class of weapons of mass destmction (WMD). Radiation (Kang et al., 2006), bacterial infections (e.g., anthrax) (Hanna et al., 1994 Kuhn et al., 2006), viral infections (e.g., influenza) (Ghezzi and Ungheri, 2004), and ricin (Kumar et al., 2003 Suntres et al., 2005) exposures also induce OS as part of the host pathogen response, which is acute inflammation. 

The activation of nuclear transcription factors has been shown to be necessary for the mechanism by which oxLDLs increase the expression of genes involved in the cell growth, differentiation, and prolifraative responses observed in atherosclerosis. In fact, it has been demonstrated that oxLDLs stimulate activator protein-1 (AP-1) DNA-binding activity in fibroblasts, SMCs, and ECs, possibly via JNKs and ERKs, and that lipid peroxidation products participates in this phenomenon. The stimulation of DNA-binding activity of another redox-sensitive transcription factor, nuclear factor k B (NF-kB), by oxLDL has also been described. ... 

The redox sensitive transcription factor NF-kB is responsible for mediating a number of stress responses, most notably inflammation and cell survival [508]. Extracellular and intracellular stimuli transmit their signals to the NF-kB/IkB complex via IkB kinases (IKKs), which phosphorylate IkB to mark it for degradation. NF-kB can then translocate to the nucleus and activate or repress genes involved in cell stress, survival, death, and differentiation. 

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