2 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 tran scriptional promoter for an early enzyme of the pathway, 3-hydroxy-3-m ethylglutaryl coenzyme A synthase, is shown to be activated by the gro wth 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 t here are two separate cis-acting sites that bind AP-1 and both are req uired for maximal stimulation. We further show that in AP-1-deficient cells ectopic expression of AP-1 stimulates synthetic promoters contai ning two copies of each synthase element upstream of a minimal promote r. The physiological rationale of having both end product repression a nd direct activation by growth stimulatory cues is discussed.