Abstract: AP-2 is a vertebrate transcription factor expressed in neural crest cells and their derivative tissues, including the adrenal medulla, where epinephrine is produced. AP-2 is shown to stimulate expression of the gene encoding the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT). However, stimulation of the PNMT gene by AP-2 requires glucocorticoids and appears to be mediated through the interaction of AP-2 with activated type II glucocorticoid receptors. Mutation of AP-2 and/or glucocorticoid receptor binding elements within the PNMT promoter disrupts the ability of AP-2 and glucocorticoids to induce PNMT promoter activity. These findings suggest, in the case of PNMT, that AP-2 stimulates gene expression through a novel glucocorticoid-dependent mechanism.