In mammalian melanocytes, melanin synthesis is controlled by tyrosinase, the critical enzyme in the melanogenic pathway. We and others showed that the stimulation of melanogenesis by cAMP is due to an increased tyrosinase expression at protein and mRNA levels. However, the molecular events connecting the rise of intracellular cAMP and the increase in tyrosinase activity remain to be elucidated. In this study, using B16 melanoma cells, we showed that cAMPelevating agents stimulated mitogen-activated protein (MAP) kinase, p44mapk . This effect was mediated by the activation of MAP kinase kinase. cAMP-elevating agents induced a translocation of p44 mapk to the nucleus and an activation of the transcription factor AP-1. cAMP-induced AP-1 contained FOS-related antigen-2 in association with JunD, while after phorbol ester stimulation AP-1 complexes consist mainly of JunD/c-Fos heterodimers. In an attempt to connect these molecular events to the control of tyrosinase expression that appears to be the pivotal point of melanogenesis regulation, we hypothesized that following its activation by cAMP, p44 mapk activates AP-1. Then AP-1 could stimulate tyrosinase expression through the interaction with specific DNA sequences present in the mouse tyrosinase promoter.In melanocytes and melanoma cells, melanin synthesis is controlled by a cascade of enzymatic reactions regulated at the level of tyrosinase. This enzyme synthesizes dopaquinone from tyrosine and appears to control the rate-limiting step of melanogenesis. Melanin synthesis is stimulated by a large array of effectors including 1-oleyl-2-acetyl-glycerol (1), ultraviolet B radiations (2), and cAMP-elevating agents (forskolin, IBMX, 1 ␣-MSH) (3-5). Few data are available concerning the molecular mechanisms triggered by these melanogenic agents. Protein kinase C was thought to be involved in the induction of melanogenesis by 1-oleyl-2-acetyl-glycerol and ultraviolet B radiations (6, 7). However, a recent report of Carsberg et al. (8) has shown that the stimulation of melanogenesis by these agents was not affected by RO485, a potent inhibitor of protein kinase C. While the role of protein kinase C in the induction of melanogenesis remains controversial, compelling data have shown that cAMP-elevating agents stimulate melanogenesis in both melanocytes and melanoma cells, indicating that the cAMP pathway plays a key role in the regulation of melanogenesis (3-5). The effect of cAMP on melanogenesis is due to a stimulation of tyrosinase activity. This appears to be the consequence of an augmentation of enzymatic activity of preexisting tyrosinase (4, 9) following post-translational modifications such as (i) phosphorylation or glycosylation (10), (ii) association with an activator (11, 12), and (iii) dissociation from an inhibitor (13). Alternatively, cAMP was shown to increase tyrosinase mRNA (14, 15), resulting in an augmentation of tyrosinase amount, suggesting that cAMP stimulates tyrosinase transcription (16). However, the molecular events connecting the stimulation of t...