Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

M Ozaki; S Haga; H Q Zhang; K Irani; S Suzuki

doi:10.1038/sj.cdd.4401172

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Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

Journal article

Open access

Peer reviewed

Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

M Ozaki, S Haga, H Q Zhang, K Irani and S Suzuki

Cell death and differentiation, Vol.10(5), pp.508-515

05/2003

DOI: 10.1038/sj.cdd.4401172

PMID: 12728249

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Abstract

Rac1-regulated reactive oxygen species (ROS) production has been implicated in apoptosis. In contrast, pleiotropic protein kinase Akt protects against apoptosis. However, the pro- and antiapoptotic mechanisms of rac1 and Akt, respectively, and the intersection between these mechanisms are incompletely understood. In a model of oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in primary hepatocytes, activation of the PI3-K Akt axis by the prosurvival hepatocyte growth factor (HGF) inhibited H/R-stimulated rac1 activation and intracellular ROS production, and suppressed apoptosis. Suppression of PI3-K or Akt activity abrogated the inhibitory effect of HGF on rac1 activity and rac1-regulated oxidative stress. Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1-regulated ROS production. These findings demonstrate that growth factor-stimulated activation of PI3-K-Akt is necessary and sufficient to suppress intracellular oxidative stress and apoptosis by inhibiting activation of pro-apoptotic, prooxidative rac1 GTPase.

Mutation

Cell Hypoxia - physiology

Reactive Oxygen Species - metabolism

Apoptosis - drug effects

Humans

Oxidative Stress - physiology

Rats, Inbred Lew

Male

Phosphatidylinositol 3-Kinases - metabolism

Hepatocytes - metabolism

Hepatocyte Growth Factor - pharmacology

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Hepatocytes - cytology

Time Factors

Protein-Serine-Threonine Kinases - antagonists & inhibitors

Proto-Oncogene Proteins

Phosphorylation - drug effects

Cell Survival - physiology

Hepatocytes - drug effects

Protein-Serine-Threonine Kinases - metabolism

Cell Survival - drug effects

Cells, Cultured

Protein-Serine-Threonine Kinases - genetics

Rats

Enzyme Activation - drug effects

Phosphatidylinositol 3-Kinases - genetics

Proto-Oncogene Proteins c-akt

Animals

Androstadienes - pharmacology

Signal Transduction - drug effects

Signal Transduction - physiology

Apoptosis - physiology

Oxidative Stress - drug effects

rac1 GTP-Binding Protein - metabolism

rac1 GTP-Binding Protein - genetics

Details

Title: Subtitle: Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1
Creators: M Ozaki - Bioengineering Laboratory, Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan. mozaki@nch.go.jp
S Haga
H Q Zhang
K Irani
S Suzuki
Resource Type: Journal article
Publication Details: Cell death and differentiation, Vol.10(5), pp.508-515
Publisher: England
DOI: 10.1038/sj.cdd.4401172
PMID: 12728249
ISSN: 1350-9047
eISSN: 1476-5403
Language: English
Date published: 05/2003
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047781002771

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