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.