Oxidants in signal transduction: impact on DNA integrity and gene expression.
Physiological stimuli using reactive oxygen species (ROS) as second messengers caused nucleotide-specific base modifications in the hypoxic response element of the VEGF gene in lung vascular cells, with the 3' guanine of the HIF-1 DNA recognition sequence uniformly targeted. Modeling this effect by replacing the targeted guanine with an abasic site increased incorporation of HIF-1 and the bi-functional DNA repair enzyme and transcriptional coactivator, Ref-1/Ape1, into the transcriptional complex and engendered more robust reporter gene expression. Oxidants generated in the context of physiological signaling thus affect nuclear DNA integrity and may facilitate gene expression by optimizing DNA-protein interactions.
Ziel
Kathryn A
KA
University of South Alabama College of Medicine, Department of Pharmacology and Center for Lung Biology, Mobile, AL 36688, USA.
Grishko
Valentina
V
Campbell
Clayton C
CC
Breit
Jeffrey F
JF
Wilson
Glenn L
GL
Gillespie
Mark N
MN
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006147:Guanine / Q000737:chemistry; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D016877:Oxidants / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D016877:Oxidants; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D006147:Guanine; D004247:DNA; D013917:Thrombin