Heme oxygenase-1: molecular mechanisms of gene expression in oxygen-related stress.
Disturbances of intracellular redox equilibrium may alter eukaryotic gene expression patterns in the manifestation of an adaptive stress response. The inducible heme oxygenase-1 gene, ho-1, responds dramatically to changes in cellular redox potential provoked by multiple agents (oxidants, xenobiotics, reactive oxygen species, nitric oxide, and ultraviolet-A radiation) as well as deviations in oxygen tension in excess or deficit of normal physiological levels. This dual response to hyperoxic and hypoxic states renders ho-1 an intriguing model system for studying oxygen-regulated gene expression. The complexation or depletion of reduced glutathione apparently represents an underlying mechanism by which oxidants trigger the response. Chelatable iron levels also influence the induction of ho-1 as evidenced by the inhibitory effects of iron-chelating compounds. Redox-sensitive protein kinase cascades (e.g., mitogen-activated protein kinases) participate in ho-1 regulation. Recent progress in understanding ho-1 transcription has identified two distal enhancer regions (E1, E2) in the mouse ho-1 gene that mediate the response to many inducing conditions. This review will examine the potential roles of iron, glutathione, and reactive oxygen species in the upstream events leading to ho-1 activation following oxygen related stress.
Ryter
Stefan W
SW
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, MUH628NW, 3459 Fifth Ave., Pittsburgh, PA 15213, USA. Ryters@msx.upmc.edu
Choi
Augustine M K
AM
D000818:Animals; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D007501:Iron; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005978:Glutathione