The role of reciprocal activation of cAbl and Mst1 in the Oxidative death of cultured astrocytes

Sook Jeong Lee, Bo Ra Seo, Eui Ju Choi, Jae Young Koh

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The protein kinase Mst1 (mammalian Sterile 20-like kinase 1) likely plays a role in oxidative neuronal cell death as a target of its activator, cAbl. We previously found that H2O2-induced death of astrocytes is mediated by cAbl in a metallothionein-3 (Mt3)-dependent manner. In the present study, we examined a possible role for Mst1 in the oxidative death of astrocytes. Treatment of cortical astrocytes with 170 μM H2O2 activated Mst1. Knockdown of Mst1 reduced H2O2-induced cell death, indicating that Mst1 activation contributes to astrocytic cell death. STI571, an inhibitor of cAbl, blocked induction/activation of Mst1 and H2O2-induced cell death. However, Mst1 silencing also inhibited induction/activation of cAbl, suggesting that the two kinases are regulated by a reciprocal activating mechanism. The zinc chelator TPEN blocked induction/activation of cAbl and Mst1, indicating that these phenomena are dependent on the rise of intracellular zinc. Moreover, H2O2 exposure did not increase free zinc levels in Mt3-null astrocytes, suggesting that the increased levels of free zinc were largely from Mt3. Consistent with the involvement of FoxO1/3, which may play a role in the Mst1-cell death cascade, we found an increase in the level of phosphorylated FoxO1/3 in H2O2-treated astrocytes. Moreover, inhibition of cAbl or Mst1 reversed this effect. The present results suggest the interesting possibility that cAbl and Mst1 are reciprocally activated under oxidative stress conditions in astrocytes. Both kinases appear to be regulated by changes in the levels of free zinc originating from Mt3 and contribute to oxidative cell death through a FoxO-dependent mechanism.

Original languageEnglish
Pages (from-to)639-648
Number of pages10
JournalGLIA
Volume62
Issue number4
DOIs
Publication statusPublished - 2014 Apr 1

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Astrocytes
Cell Death
Zinc
Phosphotransferases
Chelating Agents
Protein Kinases
Oxidative Stress
growth inhibitory factor

Keywords

  • Astrocytic death
  • CAbl
  • Metallothioneins
  • Oxidative injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

The role of reciprocal activation of cAbl and Mst1 in the Oxidative death of cultured astrocytes. / Lee, Sook Jeong; Seo, Bo Ra; Choi, Eui Ju; Koh, Jae Young.

In: GLIA, Vol. 62, No. 4, 01.04.2014, p. 639-648.

Research output: Contribution to journalArticle

Lee, Sook Jeong ; Seo, Bo Ra ; Choi, Eui Ju ; Koh, Jae Young. / The role of reciprocal activation of cAbl and Mst1 in the Oxidative death of cultured astrocytes. In: GLIA. 2014 ; Vol. 62, No. 4. pp. 639-648.
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