Two separate sites contribute to AP-1 activation of the promoter for 3-hydroxy-3-methylglutaryl coenzyme A synthase

Metabolic flux into the mevalonate pathway is regulated by end product repression and cell growth. In the experiments reported here the transcriptional promoter for an early enzyme of the pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase, is shown to be activated by the growth stimulatory agent tetraphorbol acetate (TPA). We show that TPA has a direct stimulatory action on the promoter and further that this is mediated by the AP-1 transcription factor. In addition, we show that there are two separate cis-acting sites that bind AP-1 and both are required for maximal stimulation. We further show that in AP-1-deficient cells ectopic expression of AP-1 stimulates synthetic promoters containing two copies of each synthase element upstream of a minimal promoter. The physiological rationale of having both end product repression and direct activation by growth stimulatory cues is discussed.