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Regulation of STAT-3 and STAT-6 by Transient Oxidative Stress in Rat Brain Astrocytes

Other Title
일시적 산화자극에 노출된 쥐신경성상세포에서의 STAT-3와 STAT-6의 조절기전에 관한 연구
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Doctor (2009)
"STAT family of transcription factors mediate in a variety of cellular processes, such as immune response, differentiation, cell survival, proliferation, or oncogenesis, following a series of extracellular signaling such as cytokine, growth factor, and hormone signaling. Accumulating evidence also supports a role for STAT proteins in mediating the cellular response to oxidative stress. Nevertheless, the regulation and the role of STAT proteins in brain oxidative stress still remain a poorly understood. Here, I determined the molecular mechanisms of indivisual STAT regulation and those governing how STAT proteins exerts its function under brain oxidative stress conditions using cultured rat brain astroctyes. The present study has shown that individual STAT proteins are differently regulated to H2O2-mediated oxidative stress. Fistly I report that H2O2 induced a decrease in the steady state level of STAT-3 phosphorylation by SHP-2 activation through lipid raft. In the presence of H2O2, SHP-2 formed a complex with STAT-3, and reduced the steady-state STAT-3 phosphorylation level. H2O2 triggered SHP-2 phosphorylation in a time- and dose-dependent manner, and led to its translocation into lipid rafts. H2O2-mediated SHP-2 phosphorylation and translocation were inhibited by filipin III, a lipid raft-disrupting agents. Interestingly, the effect of H2O2 on SHP-2 phosphorylation was cell type-specific. Remarkably, SHP-2 phosphorylation was induced strongly by H2O2 in astrocytes, but barely detectable in microglia. Secondly, I also report that H2O2 induced rapid STAT-6 activation via c-Src/JAK pathway contributed to the COX-2 dependet PGE2 production in brain astrocytes. I showed that H2O2 induced STAT6 phosphorylation was accompanied by it’s nuclear translocation and DNA binding activity. Experiments using pharmacological inhibitors and siRNA demonstrated that H2O2-induced STAT-6 phosphorylation was mediated by c-Src/JAK pathways upstreams. In addition, transfection with STAT-6 siRNA and EMSA using oligonucleotide probe containing COX-2 specific STAT-6 binding consensus sequence revealed that STAT-6 required for mediating COX-2 expression and PGE2 production in H2O2-treated astrocytes. In addition performing incubation experiment of microglia with ACM, I determined that PGE2 released from H2O2 treated-astrocytes functioned as paracrine mediator in deactivation of microglia. Finally, I showed that STAT-6 could be activated in a ROS-dependent manner and involved in COX-2 induction in the brain astrocytes under H/R condition. These results may indicate that STAT-6-COX-2 pathway is induced whenever ROS-mediated oxidative stress take place.

Taken together, given the specific function of each STAT protein in a variety of cellular processes, understanding of the regulation and the role of indivisual STAT under brain oxidative stress condition may lead to the development of specific therapeutic strategies for neuronal oxidative damage.

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