Rac1 regulates stress-induced, redox-dependent heat shock factor activation.
The signaling pathway by which environmental stresses activate heat shock factors (HSFs) is not completely understood. We show that the small GTPase rac1, and Rac1-regulated reactive oxygen species (ROS) play an important role in stress-stimulated heat shock response. A dominant-negative allele of Rac1 (Rac1N17) inhibits the hypoxia/reoxygenation and sodium arsenite-induced transcriptional activity of HSF-1 and the transcription of heat shock protein 70. Rac1N17 also suppresses the production of intracellular ROS induced by hypoxia/reoxygenation or sodium arsenite. Moreover, direct suppression of intracellular ROS levels by antioxidants decreases stress-stimulated HSF activity. However, expression of a constitutively active mutant of Rac1 (Rac1V12) in the absence of extracellular stresses does not increase intracellular ROS levels or induce the heat shock response. These results show that Rac1 is a necessary but insufficient component of the stress-induced signaling pathway that leads to ROS production, activation of HSFs, and transcription of heat shock proteins.
Ozaki
M
M
Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Deshpande
S S
SS
Angkeow
P
P
Suzuki
S
S
Irani
K
K
D000256:Adenoviridae / Q000235:genetics; D000483:Alleles; D018053:Arsenites / Q000494:pharmacology; D015152:Blotting, Northern; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D017670:Sodium Compounds / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism* / Q000502:physiology*
D018053:Arsenites; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D014157:Transcription Factors; C017947:sodium arsenite; D004247:DNA; D006861:Hydrogen Peroxide; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020830:rac1 GTP-Binding Protein; D010100:Oxygen