Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus

Jie Zhao, Dong Sheng Pei, Quanguang Zhang, Guang Yi Zhang

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

JNK signaling pathway is activated and involved in the selective neuronal death in the hippocampal CA1 subfield following cerebral ischemia. However, little is known about upstream partner controlling the pathway. Here we reported that ischemia/reperfusion significantly elevated Cdc42 activity, enhanced assembly of the Cdc42-MLK3 complex and activation of JNK pathway. Most importantly, knock-down endogenous Cdc42 selectively suppressed the MLK3/MKK7/JNK3 cascade, and subsequently blocked the phosphorylation of c-Jun and FasL expression. Meanwhile, Bcl-2 was inactivated and the release of cytochrome c was diminished. These alterations eventually perturbed the caspase-3 activation as well as post-ischemic neuronal cell death. Taken together, our findings strongly suggest that Cdc42 serves as an upstream activator and modulates JNK-mediated apoptosis machinery in vivo, which ultimately results in neuronal apoptosis via nuclear and non-nuclear pathways. Thus, Cdc42 may be a potential therapeutic target in ischemic brain injury.

Original languageEnglish (US)
Pages (from-to)831-843
Number of pages13
JournalCellular Signalling
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

Fingerprint

MAP Kinase Signaling System
Reperfusion
Hippocampus
Down-Regulation
Apoptosis
Cytochromes c
Brain Ischemia
Caspase 3
Brain Injuries
Cell Death
Ischemia
Phosphorylation
Therapeutics

Keywords

  • AS-ODNs
  • Cdc42
  • Cerebral ischemia
  • JNK3
  • MLK3
  • Neuroprotection

ASJC Scopus subject areas

  • Cell Biology

Cite this

Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. / Zhao, Jie; Pei, Dong Sheng; Zhang, Quanguang; Zhang, Guang Yi.

In: Cellular Signalling, Vol. 19, No. 4, 01.04.2007, p. 831-843.

Research output: Contribution to journalArticle

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