Transcriptional Regulation of the Human Leukotriene C₄ Synthase Promoter

Abstract

The cysteinyl leukotrienes are a class of molecules originally known as the slow-reacting substances of anaphylaxis (SRS-A). Leukotriene (LT)C₄, the parent compound of the group, together with its derivatives LTD₄ and LTE₄ cause increased mucus secretion, vascular permeability, and smooth muscle constriction. The pathologic role of the cysteinyl leukotrienes in bronchial asthma has been established by their chronic overproduction in the airways of patients with asthma and by the relief experienced by such patients after the administration of agents that attenuate leukotriene elaboration or their receptor-mediated actions [1]. LTC₄ synthase (LTC₄S), an 18-kD integral membrane protein, is a key enzyme in the biosynthesis of the cysteinyl leukotrienes. It conjugates LTA₄ with reduced glutathione to form LTC₄. LTC₄S is expressed predominantly in mast cells, basophils, and eosinophils, a subset of the monocyte and myeloid lineages important for allergy and inflammation. However, the mechanisms controlling the cell-specific expression of LTC₄S are not well understood. Our recent study of the LTC₄S promoter indicated that several cis-acting elements are involved in the transcription of this TATA-less gene. This article reviews constitutive and induced expression of LTC₄S in various cells and focuses on the delineation of cis-acting elements and the identification of transcription factors that transactivate the human LTC₄S gene promoter.