Placental leucine aminopeptidase (P-LAP) is located preferentially in syncytiotrophoblasts in human placenta. Here we investigated P-LAP expression and the regulatory mechanisms in BeWo choriocarcinoma cells with forskolin (FSK)-induced differentiation. Morphologically differentiated cells revealed enhanced P-LAP staining. FSK significantly increased P-LAP activity and mRNA. Deletion or mutation of activator protein-2 (AP-2) binding site in the footprint-3 (-216 to -172) of P-LAP promoter abrogated the stimulatory effects of FSK on luciferase activity of the construct -216/+49. In AP-2-deficient Hep-G2 cells, FSK failed to stimulate luciferase activity of the construct -216/+49. Among the isoforms, BeWo expressed AP-2alpha and AP-2gamma, while FSK increased only AP-2alpha. These results suggest differentiation-dependent P-LAP expression in trophoblasts, which involves increased AP-2alpha binding.