Regulation of the Expression of Heme Oxygenase-1: Signal Transduction, Gene Promoter Activation, and Beyond.

Significance: Heme oxygenase-1 (HO-1) is a ubiquitous 32-kDa protein expressed in many tissues and highly inducible. They catalyze the degradation of the heme group and the release of free iron, carbon monoxide, and biliverdin; the latter converted to bilirubin by biliverdin reductase. Its role in the regulation of cellular homeostasis is widely documented. Studying regulation of HO-1 expression is important not only to understand the life of healthy cells but also the unbalances in cell metabolism that lead to disease. Recent Advances: The regulation of its enzymatic activity depends heavily upon changes in expression studied mainly at the transcriptional level. Current knowledge regarding HO-1 gene expression focuses primarily on transcription factors such as Nrf2 (nuclear factor erythroid 2-related factor 2), AP-1 (activator protein-1), and hypoxia-inducible factor, which collect signal transduction pathway information at the HO-1 gene promoter. Understanding of gene expression regulation is not limited to transcription factor activity but also involves an extended range of post- or cotranscriptional regulated events. Critical Issues: In addition to the regulation of gene promoter activity, alternative splicing, alternative polyadenylation, and regulation of messenger RNA stability play critical roles in changes in HO-1 gene expression levels, involving specific factors, proteins, and microRNAs. All potential targets for diagnosis or treatment of diseases are related to HO-1 dysregulation. Future Directions: Unbalances in the tightly regulated gene expression mechanisms lead to cell transformation and cancer development. Knowledge of these events and signal transduction cascades triggered by oncogenes in which HO-1 plays a critical role is of upmost importance for research in this field.