Transcriptional Regulation of the Heme Oxygenase-1 Gene Via the Stress Response Element Pathway

Abstract

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.