Identification of the promoter elements involved in the sterol-mediated transcriptional regulation of farnesyl diphosphate synthase

Farnesyl diphosphate (FPP) synthase is a prenyltransferase in the isoprene biosynthetic pathway. The enzyme catalyzes the synthesis of the fifteen carbon (C{dollar}sb{lcub}15{rcub}{dollar}) farnesyl diphosphate by the sequential condensation of dimethylallyl diphosphate (DMAPP) with two molecules of isopentenyl diphosphate (IPP) (Poulter and Rilling, 1983). Farnesyl diphosphate serves as a precursor to both sterol and nonsterol isoprene compounds and is required for the prenylation of several important polypeptides involved in diverse cellular functions.; Differential hybridization was originally used to isolate the FPP synthase cDNA from rat liver (Clarke et al., 1987). The mRNA levels of FPP synthase were shown to be highly regulated in response to cellular sterol levels in both the rat and cultured cell (Clarke et al., 1987, Rosser et al., 1989). The changes in FPP synthase mRNA levels were similar to those observed for two other genes involved in isoprene biosynthesis, 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase (Clarke et al., 1987, Rosser et al., 1989).; We have isolated the functional gene encoding FPP synthase from rat liver and characterized the cis-acting promoter elements involved in both its sterol-mediated and normal transcriptional regulation (Spear et al., 1992). Deletion and mutational analyses of the promoter have identified a 34 base pair element that is involved in the transcriptional induction of the FPP synthase gene in cells deprived of sterols. Within this region, there are no sequences exhibiting high sequence identity to the sterol regulatory element (SRE-1) previously identified in the promoters of other sterol regulated genes (Goldstein and Brown., 1990). The current results suggest that the sterol-mediated transcriptional regulation of FPP synthase is facilitated by a novel mechanism. The elucidation of the element(s) and factor(s) involved in this mechanism will contribute to the knowledge concerning the transcriptional regulation of genes involved in cholesterogenesis and may have important therapeutic value in the design of drugs involved in lowering plasma cholesterol levels and preventing certain types of cancer.