We have recently identified an Ets element controlling over 90% of the basal expression of the human presenilin 1 (PS1) gene. We have also shown that Ets1 and Ets2 act as transactivators of the PS1 gene by cotransfection experiments in SK-N-SH neuronal cells. The PS1 gene is widely but differentially expressed across tissues and the expression in brain appears to be restricted to neurons. To gain further insight into the regulation of the gene we have examined the regulation of PS1 by 12-O-tetradecanoylphorbol 13-acetate (TPA). SK-N-SH neuronal cells were treated with 0.2 μM TPA for 30 min to 24 h and the level of expression of the endogenous PS1 gene was measured by Northern blot analysis. A two- to threefold increase in the level of PS1 mRNA appeared 4-8 h after the addition of TPA. A similar increase in transcription activity was observed in nuclear run off experiments, indicating that the increased mRNA level results from an activation in the initiation of transcription of PS1. Consistently, TPA also increased the level of PS1 protein. No activation of the PS1 endogenous gene by TPA was observed in hepatoma HepG2 cells. Next we tested the effect of TPA on the expression of the PS1 promoter by transfecting fusion genes including various fragments of the PS1 promoter linked to a CAT reporter into SK-N-SH cells. TPA also stimulated the expression of the PS1CAT constructs. Generally wild type constructs -687/+178, -118/+178, -22/+178 including the short -35/+6 fragment showed a minor two- to threefold activation by TPA. Point mutations eliminating the -10 Ets motif or the -6 CREB/AP1 motif did not decrease the stimulation by TPA. Thus TPA appears to activate the transcription of the PS1 gene by a mechanism which does not require these elements.