Multiple sterol regulatory elements in promoter for hamster 3-hydroxy-3-methylglutaryl-coenzyme A synthase.

Abstract

Through substitution mutagenesis and gene transfer experiments in cultured cells, we have identified three sequences in the 5' flanking region of the gene for hamster 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase that are required for sterol-mediated regulation of transcription. Point mutations in any one of these sequences largely prevented the increase in transcription that normally follows cellular sterol depletion. These mutations did not alter the low level of transcription that occurs in the presence of sterols. Two of the three sterol regulatory sequences contain an octanucleotide that shows a 7/8-base pair match with a sequence that was previously identified as a sterol regulatory element in the genes for HMG-CoA reductase and the low density lipoprotein receptor, both of which are induced by sterol deprivation. The third sterol regulatory region in the HMG-CoA synthase promoter shows only a low-level match with the other sterol regulatory elements. The current data suggest that the sterol regulatory elements in the HMG-CoA synthase promoter operate by a conditional positive mechanism: in the absence of sterols, regulatory proteins bind to these elements and stimulate transcription; in the presence of sterols, the regulatory proteins are inactivated and transcription decreases to the basal rate.