The 5' upstream regulatory region of the gene encoding the rat amyloid precursor protein (APP) was cloned and sequenced. It lacks both a TATA box and a CAAT box, has a high G + C content (68%), is 89% homologous to the corresponding region of the mouse APP gene, and 82% homologous to the corresponding region of the human APP gene. This region contains putative regulatory elements both 5' and 3' to the probable transcription start point (tsp). There are consensus DNA sites for the binding of SP1, AP2, AP4 and GC factor (GCF) proteins, and two GC boxes with the consensus sequence, 5'-GGGYGCRG. Potential regulatory sites with only a single mismatch to the consensus sequences include three SP1, one AP1, five AP2, and two GCF sites, as well as one GC box. There are also six potential stem-loop secondary structures (SSS) near the probable tsp. A consecutive series of elements, consisting of a GC box, AP2 site, three SSS, two SP1 sites, and AP4, AP1 and GCF sites just upstream from the probable tsp, are well-conserved between the rat, mouse and human sequences. An additional AP2 site, two GC boxes, and two additional SSS appear to be conserved between species. However, two possible rat SP1 sites, three possible rat AP2 sites, and two possible rat GCF sites are lacking in the human. On the other hand, the rat sequence is missing four potential SP1 sites, four potential AP2 sites, and nine potential GC boxes which are found in the human sequence.(ABSTRACT TRUNCATED AT 250 WORDS)