GSK-3β-induced ASK1 stabilization is crucial in LPS-induced endotoxin shock

Kyung Tae Noh, Yeong Min Park, Ssang Goo Cho, Eui Ju Choi

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Glycogen synthase kinase-3β (GSK-3β), 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-3β In addition, compared with L929 control cells, ASK1 protein was reduced in L929 cells stably expressing Wnt-3a and in which β-catenin was active, due to the inhibition of GSK-3β activity. GSK-3β inhibition-mediated ASK1 reduction was also confirmed by reduced ASK1 in GSK-3β-deficient mouse embryo fibroblasts (MEFs) and MCF7 GSK-3β siRNA cells. Furthermore, ASK1 protein stability was also attenuated in MCF7 GSK-3β siRNA cells compared with GFP control cells. Consistent with stability data, a much stronger ubiquitination of ASK1 was observed in cells in which GSK-3β was knocked down. These findings suggest that GSK-3β crosstalks with p38 kinase via the regulation of ASK1 protein stability in endotoxemia.

Original languageEnglish
Pages (from-to)1663-1668
Number of pages6
JournalExperimental Cell Research
Volume317
Issue number12
DOIs
Publication statusPublished - 2011 Jul 15

Fingerprint

MAP Kinase Kinase Kinase 5
Glycogen Synthase Kinase 3
Endotoxins
Lipopolysaccharides
Shock
Endotoxemia
Phosphotransferases
Protein Stability
Small Interfering RNA
Catenins
Toll-Like Receptor 4
Ubiquitination
Septic Shock

Keywords

  • ASK1
  • Endotoxemia
  • GSK-3β
  • P38
  • Stability

ASJC Scopus subject areas

  • Cell Biology

Cite this

GSK-3β-induced ASK1 stabilization is crucial in LPS-induced endotoxin shock. / Noh, Kyung Tae; Park, Yeong Min; Cho, Ssang Goo; Choi, Eui Ju.

In: Experimental Cell Research, Vol. 317, No. 12, 15.07.2011, p. 1663-1668.

Research output: Contribution to journalArticle

Noh, Kyung Tae ; Park, Yeong Min ; Cho, Ssang Goo ; Choi, Eui Ju. / GSK-3β-induced ASK1 stabilization is crucial in LPS-induced endotoxin shock. In: Experimental Cell Research. 2011 ; Vol. 317, No. 12. pp. 1663-1668.
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