Regulation of transcription of the human presenilin-1 gene by Ets transcription factors and the p53 protooncogene

The expression of the human presenilin-1 cellular gene is suppressed by the p53 protooncogene. The rapid kinetic of the down-regulation has suggested that it may result from a primary mechanism. We show here that p53 also sup presses the transcription of a presenilin-1 promoter-chloramphenicol acetyl transferase reporter synthetic gene in transient infection assays in neurob lastoma (SK-N-SH) and hepatoma (HepG2) cell lines. Only:a minimum promoter including sequences from -35 td + 6 from the transcription initiation is su fficient to confer down-regulation. We have previously defined a crucial DN A element controlling 90% of the expression of the gene:within the same sho rt area, and the identification of the transcription factors involved shoul d also provide insights into the regulation of PSI by p53. This region,cont ains an Ets transcription factor binding motif, and a a-base pair alteratio n within the core sequence (GGAA to TTAA) of the Ets consensus also reduced transcription by more than 90%. We now show that Ets1 and Ets2: indeed tra nsactivate a PSI promoter-chloramphenicol acetyltransferase reporter includ ing the (-35 to +6):fragment. Furthermore, in vitro translated Ets2 binds s pecifically to the -10 Ets motif in electrophoretic mobility shift assays. Therefore, Ets1/2 factors bind specifically to the -10 Ets element and acti vate PS1 transcription. We also show that the coactivator p300 enhances the activation by Ets1 and Ets2 as well as the repression by p53. p300 is know n to interact with p53 as well as with Ets1 and Ets2. We show that p53 does not bind directly to the PSI promoter. Hence the repression of PS1:transcr iption by p53 is likely to be mediated through protein-protein interactions .