Transcriptional regulation of the squalene synthase gene (ERG9) in the yeast Saccharomyces cerevisiae

The ergosterol biosynthetic pathway is a specific branch of the mevalonate pathway. Since the cells requirement for sterols is greater than for isopre noids, sterol biosynthesis must be regulated independently of isoprenoid bi osynthesis. In this study we explored the transcriptional regulation of squ alene synthase (ERG9) in Saccharomyces cerevisiae, the first enzyme dedicat ed to the synthesis of sterols. A mutant search was performed to identify g enes that were involved in the regulation of the expression of an ERG9-lacZ promoter fusion. Mutants with phenotypes consistent with known sterol bios ynthetic mutations (ERG3, ERG7, ERG24) increased expression of ERG9. In add ition, treatment of wild-type cells with the sterol inhibitors zaragozic ac id and ketoconazole, which target squalene synthase and the C-14 sterol dem ethylase respectively, also caused an increase in ERG9 expression. The data also demonstrate that heme mutants increased ERG9 expression while anaerob ic conditions decreased expression. Additionally, the heme activator protei n transcription factors HAP1 and HAP2/3/4, the yeast activator protein tran scription factor yAP-1, and the phospholipid transcription factor complex I NO2/4 regulate ERG9 expression. ERG9 expression is decreased in hap1, hap2/ 3/4, and yap-1 mutants while ino2/4 mutants showed an increase in ERG9 expr ession. This study demonstrates that ERG9 transcription is regulated by sev eral diverse factors, consistent with the idea that as the first step dedic ated to the synthesis of sterols, squalene synthase gene expression and ult imately sterol biosynthesis is highly regulated. (C) 1999 Elsevier Science B.V, All rights reserved.