We have identified DNA sequences required for the expression of the presenilin 1 (PS1) gene. A promoter region has been mapped in SK-N-SH cells and includes sequences between -118 and + 178 flanking the major initiation site (+ 1). The PS1 gene is also efficiently transcribed in the SH-SY5Y subclone of SK-N-SH cells. However the promoter appears to be utilized in alternative ways in both cell types. Sequences both upstream as well as downstream from the initiation site mapped in SK-N-SH cells were shown by 5′- and 3′-deletion analysis to play a crucial role in both cell lines. However, in SH-SY5Y cells either upstream or downstream sequences are sufficient to direct transcription, whereas in SK-N-SH cells 5′-deletions past the + 1 site eliminate over0 95% of transcription. Several Ets motifs (GGAA) as well as Sp1 motifs [(G/T)GGCGGRRY] are juxtaposed both upstream and downstream from + 1. To understand how the promoter may be utilized alternatively in different cell types we have examined the effect of point mutations in these elements. Altering an Ets motif at -10 eliminates 80% of transcription in SK-N-SH cells whereas the same mutation has only a minor effect in SH-SY5Y cells. Conversely, mutation of the Ets element at + 90, which eliminates 70% of transcription in SH-SY5Y cells, has a lesser effect in SK-N-SH cells. In both cell types a promoter including mutations at both -10 and + 90 sites loses over 90% transcription activity indicating the crucial importance of these two Ets motifs. The effect of Sp1 mutations appears to be similar in both cell types. Hence the differential expression in each cell type may be at least partially determined by Ets factors and the -10/+ 90 sites. We have identified several Ets factors that recognize specifically the -10 Ets motif by the yeast one-hybrid selection including avian erythroblastosis virus E26 oncogene homologue 2, Ets-like gene 1, Ets translocation variant 1 and Ets related molecule (ERM). We show here that ERM specifically recognizes Ets motifs on the PS1 promoter located at -10 as well as downstream at + 90, + 129 and + 165 and activates PS1 transcription with promoter fragments containing or not the -10 Ets site.