Ap1-like cis elements, interacting with transcription factors of the Ap1 and CREB/ATF families, were identified in the 5'-regulatory region of the human apolipoprotein A-I gene (5'-apoA-I). The elements are beyond the hepatic enhancer (-220 ÷ -110) and region -595 ÷ -192, responsible for efficient transcription in Caco2 cells. One of the elements (5'-TGAGGTCT-3', Cre/jun2/apo) occurs in 5'-apoA-I in two copies, distal (-2176 ÷-2165) and proximal (99 ÷ 106). The electrophoretic mobility shift assay was used to characterize this and two other 5'-apoA-I Ap1-like elements: 5'-TGACTCT-3' (-1798 ÷ -1791, PF1) and 5'-TGACATCA-3' (-1171 ÷ -1163, Cre/jun1). Experiments with specific antibodies identified ATF2 as a component of the complexes formed by HepG2 nuclear proteins with Cre/jun2/apo and Cre/jun1. Several 5'-apoA-I deletion derivatives were examined in HepG2 hepatoma cells (producing ApoA-I), Hutu80 duodenal adenocarcinoma cells (lacking ApoA-I production), and SK-N-SH neuroblastoma cells (carrying defective apoA-I) by the luciferase reporter assay. Combined with cell cotransfection with c-jun and mekk1 expression vectors, the assays implicated the Ap1-like elements in the tissue-specific regulation of apoA-I expression, the proximal Cre/jun2/apo element playing the major role.