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 (El, 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.