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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Bile salt-induced apoptosis involves NADPH oxidase isoform activation
Roland Reinehr1, Stephan Becker, Verena Keitel
1Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Gastroenterology
|December 14, 2005
Summary
Hydrophobic bile salts cause oxidative stress by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. This stress response triggers CD95 activation and liver cell apoptosis.
Area of Science:
- Hepatology
- Oxidative Stress
- Cell Death Signaling
Background:
- Hydrophobic bile salts are implicated in liver injury.
- Oxidative stress is a key factor in cellular damage.
Purpose of the Study:
- To elucidate the mechanisms by which hydrophobic bile salts induce hepatocyte apoptosis.
- To identify the upstream signaling events leading to CD95 activation.
Main Methods:
- Western blot analysis
- Immunocytochemistry
- Protein knockdown studies
- Fluorescence resonance energy transfer (FRET) microscopy
- Primary rat hepatocytes and Huh7 cells
Main Results:
- Taurolithocholate-3-sulfate (TLCS) induced oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, involving p47phox phosphorylation.
- Inhibition of p47phox phosphorylation or knockdown abolished TLCS-induced oxidative stress and CD95 activation.
- Oxidative stress led to c-Jun-N-terminal kinase activation, epidermal growth factor receptor (EGFR) activation, and subsequent CD95 phosphorylation and apoptosis.
- TLCS promoted EGFR/CD95 complex formation and plasma membrane trafficking, dependent on sphingomyelinase and protein kinase Czeta (PKCzeta).
Conclusions:
- Hydrophobic bile salts activate NADPH oxidase isoforms, initiating an oxidative stress response.
- This oxidative stress triggers the CD95 signaling pathway, culminating in hepatocyte apoptosis.
- Sphingomyelinase and PKCzeta are critical upstream regulators in this pathway.
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