| First Author | Noh KT | Year | 2011 |
| Journal | Exp Cell Res | Volume | 317 |
| Issue | 12 | Pages | 1663-8 |
| PubMed ID | 21515258 | Mgi Jnum | J:172662 |
| Mgi Id | MGI:5008510 | Doi | 10.1016/j.yexcr.2011.03.022 |
| Citation | Noh KT, et al. (2011) GSK-3beta-induced ASK1 stabilization is crucial in LPS-induced endotoxin shock. Exp Cell Res 317(12):1663-8 |
| abstractText | Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional kinase, is a regulator of lipopolysaccharide (LPS)-mediated septic shock. Apoptosis signal-regulating kinase 1 (ASK1) is also required for LPS-induced activation of p38, which is a crucial determinant for the production of pro-inflammatory cytokines via Toll-like receptor 4 (TLR4) in endotoxemia. Here, we show that attenuation of endotoxemia induced by GSK-3 inhibition is caused by the ASK1 reduction-mediated inhibition of p38, a representative downstream kinase of ASK1. LPS-stimulated activation of p38 was blocked by the reduction of ASK1 via the knockdown of GSK-3beta. In addition, compared with L929 control cells, ASK1 protein was reduced in L929 cells stably expressing Wnt-3a and in which beta-catenin was active, due to the inhibition of GSK-3beta activity. GSK-3beta inhibition-mediated ASK1 reduction was also confirmed by reduced ASK1 in GSK-3beta-deficient mouse embryo fibroblasts (MEFs) and MCF7 GSK-3beta siRNA cells. Furthermore, ASK1 protein stability was also attenuated in MCF7 GSK-3beta siRNA cells compared with GFP control cells. Consistent with stability data, a much stronger ubiquitination of ASK1 was observed in cells in which GSK-3beta was knocked down. These findings suggest that GSK-3beta crosstalks with p38 kinase via the regulation of ASK1 protein stability in endotoxemia. |
