Genetic variations in the 5-lipoxygenase core promoter. Description and functional implications.

Abstract

The regulation of 5-lipoxygenase (5-LO) activity occurs at multiple steps and is quite complex; each of the regulatory steps has been the subject of intense investigation. Regulation of 5-LO product output is known to occur by regulation of availability and catalytic action of 5-LO. With respect to 5-LO protein availability there are data documenting regulation at the level of gene transcription (1-4), gene translation (5), and gene product translocation within the cell (6, 7). With respect to catalytic action, regulation of 5-LO product production is known to be influenced by the availability of its major substrate arachidonic acid (8). Another mechanism regulating 5-LO catalytic activity is termed suicide inactivation and results from the oxidative inactivation of the functional enzyme by its primary catalytic product, leukotrienne A 4 (LTA 4 ). Suicide inactivation is irreversible and occurs only when 5-LO is catalytically active (9). Thus, if a cell with catalytically active 5-LO is to sustain product output, there must be a means by which to replace the inactivated enzyme. Since 5-LO output is known to be sustained, de novo production of the enzyme must take place; therefore, it is critical to examine the factors regulating 5-LO gene transcription and translation. Indeed, among these points of regulation of 5-LO gene transcription and translation, we have identified a novel mechanism potentially accounting for variability of 5-LO transcriptional regulation among individuals, namely genetic variation due to mutations in the 5-LO core promoter. We review effects of these mutations in the context of regulation of 5-LO gene transcription.