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The ability to communicate with the environment and respond to changes--particularly those of an adverse nature--within that environment is critical for cell function and survival. A key component of the overall cellular stress response includes adjustments in the gene expression program in favor of proteins that manifest activities capable of frustrating and eventually eliminating the molecular constituents of the stress condition. One protein providing such cytoprotective activity is heme oxygenase-1 (HO-1), an enzyme that catalyzes the rate-limiting reaction in heme catabolism (i.e., the oxidative cleavage of b-type heme molecules to yield equimolar quantities of biliverdin IXalpha, carbon monoxide, and iron). Because of the potent antioxidant, anti-inflammatory, and signaling properties of the reaction products, the HO-1 gene (hmox1) is frequently activated under a variety of cellular stress conditions. Cells use multiple signaling pathways and transcription factors to fine-tune their response to a specific circumstance. Among these factors, members of the heat-shock factor, nuclear factor-kappaB, nuclear factor-erythroid 2, and activator protein-1 families are arguably the most important regulators of the cellular stress response in vertebrates. Although there is functional overlap between individual families, each broadly regulates different aspects of the cellular stress response and thus, with some exceptions, modulates the expression of different sets of targets genes. To the best of our knowledge, hmox1 is unique in that it is proposed to be directly regulated by all four of these stress-responsive transcription factors. In this article we provide a review and analysis of the data supporting this proposition.

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The heme oxygenase-1 (HO-1) enzyme catalyzes the rate-limiting reaction in the catabolism of heme yielding products with pleiotropic, but ultimately, cytoprotective activities. High levels of HO-1 are frequently detected in various pathological states and generally in states of cellular oxidative stress. Induction of HO-1, regulated at the level of gene transcription, is essential for manifestation of the enzyme's cytoprotective function. Extensive analysis of the mouse gene, and to a lesser extent of the human gene, has identified a common mechanism the stress response element (StRE)/Nrf2 transcription factor pathway for gene regulation in response to a diverse array of HO-1 inducers including the substrate heme, various environmental and industrial toxins, and plant-derived polyphenolic compounds. In addition to Nrf2 complexes, numerous dimeric transcription factors bind to the StRE, permitting induction, repression and overall fine-tuning of gene activity. In principle, the multiplicity of StRE binding proteins also provides for a range of pharmaceutical targets for controlled production of the potentially therapeutic HO-1 protein.