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Suppression of Etk/Bmx protects against ischemic brain injury.

Abstract
Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of protein-tyrosine kinases, is an important regulator of signal transduction for the activation of cell growth, differentiation, and development. We have previously reported that activation of Etk leads to apoptosis in MDA-MB-468 cells. The purpose of this study was to examine the role of Etk in neuronal injury induced by H(2)O(2) or ischemia. Using Western blot analysis and immunohistochemistry, we found that treatment with H(2)O(2) significantly enhanced phosphorylation of Etk and its downstream signaling molecule Stat1 in primary cortical neurons. Inhibiting Etk activity by LFM-A13 or knocking down Etk expression by a specific shRNA increased the survival of primary cortical neurons. Similarly, at 1 day after a 60-min middle cerebral artery occlusion (MCAo) in adult rats, both phosphorylated Etk and Stat1 were coexpressed with apoptotic markers in neurons in the penumbra. Pretreatment with LFM-A13 or an adenoviral vector encoding the kinase deletion mutant Etkk attenuated caspase-3 activity and infarct volume in ischemic brain. All together, our data suggest that Etk is activated after neuronal injury. Suppressing Etk activity protects against neurodegeneration in ischemic brain.
AuthorsKai-Yun Chen, Chung-Che Wu, Cheng-Fu Chang, Yuan-Hao Chen, Wen-Ta Chiu, Ya-Hsin Lou, Yen-Hua Chen, Hsiu-Ming Shih, Yung-Hsiao Chiang
JournalCell transplantation (Cell Transplant) Vol. 21 Issue 1 Pg. 345-54 ( 2012) ISSN: 1555-3892 [Electronic] United States
PMID21929872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amides
  • LFM A13
  • Nitriles
  • RNA, Small Interfering
  • STAT1 Transcription Factor
  • Stat1 protein, rat
  • Hydrogen Peroxide
  • Bmx protein, rat
  • Protein-Tyrosine Kinases
  • Caspase 3
Topics
  • Amides (pharmacology)
  • Animals
  • Apoptosis
  • Brain Ischemia (metabolism, therapy)
  • Caspase 3 (biosynthesis)
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Cell Survival (genetics)
  • Cerebral Cortex (cytology, metabolism)
  • Hydrogen Peroxide (pharmacology)
  • Neurons (metabolism)
  • Nitriles (pharmacology)
  • Phosphorylation (drug effects)
  • Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • STAT1 Transcription Factor (metabolism)
  • Signal Transduction

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