MUC18/MCAM is a melanoma-associated cell adhesion molecule that is also occasionally found on carcinomas and other tumor types. On melanomas, MUC18 expression increases with tumor progression and is found on more than 70% of metastatic lesions. To investigate the regulation of MUC18 expression, cell lines of diverse tissue origin were exposed to cytokines, regulators of intracellular cyclic AMP (cAMP), and to phorbol ester. MUC18 expression could not be induced in negative cell lines and could only be modulated by changes in cAMP levels or by exposure to phorbol ester in positive cells. An increase in intracellular cAMP led to an up-regulation in cell surface MUC18 that was maximal at 48 h. Increased MUC18 mRNA levels were observed as soon as 4 h and were 3-fold higher than in control cells by 48 h. Exposure of the cells to phorbol ester reduced MUC18 surface expression to background levels by 24 h. This downregulation was associated with decreased mRNA levels that were apparent at 8 h. By 24 h, steady-state levels of MUC18 mRNA had been reduced by 58%. Whereas similar changes in MUC18 surface expression were observed in MUC18-expressing glioma and carcinoma cell lines, melanoma cells were more resistant to the MUC18-modulating effects of cAMP analogues and phorbol ester. These observations suggest that the strong MUC18 expression observed in advanced melanomas may reflect disturbances in the normal regulation of this molecule.