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Figure 7 | Respiratory Research

Figure 7

From: Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology

Figure 7

Schematic showing signal transduction pathways mediated by environmental stresses such as lipopolysaccharide (LPS), cytokines, hyperoxia and irradiation (UV). The transmission of the signalling cascade across the membrane (gray 'bridge' shape) is associated with the activation of upstream kinases. Small G- protein-coupled proteins, such as PAK and RAC, mediate the activation of MAPK kinase kinase (MEKK) or NF-κB inducing kinase (NIK). The pathway then bifurcates into two branches: the p38 mitogen-activated protein kinase (MAPK) pathway and the IκB/NF-κB pathway. One pathway activates IκB kinase (IKK), thereby leading to IκB phosphorylation/degradation and subsequently allowing NF-κB complex to translocate to the nucleus and promote gene expression. The other pathway involves the phosphorylation of MAPK kinase (MKK), which phosphorylates and activates MAPK (p38). This pathway is selectively blocked by the pyridinyl imidazole SB-203580. The activation of the MAPK pathway regulates the downstream activation of MAPK activating kinase (MAPKAP-K2), which phosphorylates the small heat-shock protein 27 (Hsp27) and activates the stability of transcripts of cytokines bearing the AU-rich element (ARE). The antioxidant N-acetyl-L-cysteine (NAC) provides cysteine that feeds into the biosynthetic machinery, allowing the formation of glutathione (GSH) by the action of the rate-limiting enzyme, γ-glutamylcysteine synthetase (γ-GCS). The activity of γ-GCS is irreversibly blocked by L-buthionine-(S,R)-sulfoximine (BSO). GSH is broken down to cysteine by the action of γ-glutamyl transpeptidase (γ-GT), a membrane-bound enzyme. Redox regulation of the MAPK pathway mediated by NAC is likely to implicate the blockading of the upstream kinase that leads to phosphorylation and activation of p38/(reactivating kinase, RK).

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