Metabolic flux into the mevalonate pathway is regulated by end product repression and cell growth. In the experiments reported here the transcrlptlonal 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 cls-actlng sites that bind AP-1 and both are required for maximal stimulation. We further show that in AP-1-deficient cells ectoplc 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.
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