The melanoma cell adhesion molecule was identified as a human melanoma-associated antigen that increases in expression as tumors increase in thickness and begin to acquire metastatic potential. Clinical and experimental evidences suggest that the development of metastatic capacity might be the consequence of increased melanoma cell adhesion molecule expression. The mechanisms for upregulation of the melanoma cell adhesion molecule during melanoma progression are, however, still poorly understood. In this study, we show that melanoma cell adhesion molecule expression is tightly regulated at the transcriptional level. Using a combination of CAT reporter assays and semiquantitative reverse transcriptase-polymerase chain reaction, we observed that cyclic adenosine monophosphate significantly increases transcription of the melanoma cell adhesion molecule in nonmetastatic melanoma cells. In metastatic cells, transcription of the gene was constitutive and could not be further increased by cyclic adenosine monophosphate. On the other hand, melanoma cell adhesion molecule promoter activity was impeded upon treatment with phorbol esters or in the presence of stem cell factor, a phenomenon which was protein kinase C-dependent. Promoter-deletion studies demonstrated that the first 196 nt of the melanoma cell adhesion molecule promoter region are sufficient to get full expression in metastatic melanoma cells. This fragment contains five binding sites for the transcription factor Sp1 and DNA mobility shift experiments showed direct binding of Sp1 to the promoter. In conclusion, our results indicate that Sp1 is sufficient to drive constitutive melanoma cell adhesion molecule expression in metastatic melanoma cells. In nonmetastatic cells, however, melanoma cell adhesion molecule expression is repressed and we speculate that stem cell factor/c-Kit signaling might be responsible for the control of melanoma cell adhesion molecule synthesis, and thus, perhaps, of melanoma progression and metastasis.