Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NF kappa B is a critical transcription factor involved in modulating cellular responses to environmental injuries. Tyrosine 42 phosphorylation of I kappa B alpha has been shown to mediate NF kappa B activation following hypoxia/reoxygenation (H/R) or pervanadate treatment. This pathway differs from the canonical proinflammatory pathways, which mediate NF kappa B activation through serine phosphorylation of I kappa B alpha by the IKK complex. In the present study, we investigated the involvement of c-Src in the redox activation of NFkappaB following H/R or pervanadate treatment. Our results demonstrate that pervanadate or H/R treatment leads to tyrosine phosphorylation of I kappa B alpha and NF kappa B transcriptional activation independent of the IKK pathway. In contrast, inhibition of c-Src by pp2 treatment or in c-Src (-/-) knockout cell lines, demonstrated a significant reduction in I kappa B alpha tyrosine phosphorylation and NF kappa B activation following pervanadate or H/R treatment. Overexpression of glutathione peroxidase-1 or catalase, but not Mn-SOD or Cu,Zn-SOD, significantly reduced both NF kappa B activation and tyrosine phosphorylation of I kappa B alpha. In vitro kinase assays further demonstrated that immunoprecipitated c-Src has the capacity to directly phosphorylate GST-I kappa B alpha and that this I kappa B alpha kinase activity is significantly reduced by Gpx-1 overexpression. These results suggest that c-Src-dependent tyrosine phosphorylation of I kappa B alpha and subsequent activation of NF kappa B is controlled by intracellular H(2)O(2) and defines an important redox-regulated pathway for NF kappa B activation following H/R injury that is independent of the IKK complex.
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PMID:Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. 1242 43

Disruption of mitochondrial reactive oxygen species (mtROS) homeostasis is a key factor inducing UCB-MSC senescence. Accordingly, preventing mtROS accumulation will help in suppressing the UCB-MSC senescence. In this study, we observed that the expressions of EphrinB2 and EphB2 were inversely regulated by UCB-MSC passage-dependent manner. EphB2 signaling induced mitochondrial translocation of Sirt3. The knockdown of SIRT3 inhibited the effect of EphB2 signaling in UCB-MSCs. Subsequently, EphrinB2-Fc induced the nuclear translocation of Nrf-2 via c-Src phosphorylation dependent manner, and Sirt3 expression was regulated by Nrf-2. Among Sirt3 target genes, EphB2 signaling increased MnSOD and reduced the mtROS level in UCB-MSCs. Furthermore, the deacetylase effect of Sirt3 enhanced the MnSOD activity by deacetylation at the lysine 68 residue and therapeutic effect of UCB-MSCs on skin-wound healing was increased by EphB2 activation. In conclusion, the EphB2 can serve as a novel target for the optimizing the therapeutic use of UCB-MSCs in wound repair by MnSOD-mediated mtROS scavenging through EphB2/c-Src signaling pathway and Nrf-2-dependent Sirt3 expression.
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PMID:EphB2 signaling-mediated Sirt3 expression reduces MSC senescence by maintaining mitochondrial ROS homeostasis. 2868 9