GENOMIC ORGANIZATION OF THE MELANOMA-ASSOCIATED GLYCOPROTEIN MUC18 - IMPLICATIONS FOR THE EVOLUTION OF THE IMMUNOGLOBULIN DOMAINS

The cell surface glycoprotein MUC18, a member of the immunoglobulin su perfamily and homologous to several cell adhesion molecules, is associ ated with tumor progression and the development of metastasis in human malignant melanoma. Immunohistochemical and Northern blot analysis re vealed that expression of the antigen is restricted to advanced primar y and metastatic melanomas and to cell lines of the neuroectodermal li neage. The genomic sequence encoding the cell surface antigen spans al most-equal-to 14 kb and consists of 16 exons. The organization of the gene, which is related to that of the neural cell adhesion molecule N- CAM, shows a structure where each immunoglobulin-related domain is enc oded by more than one exon. Sequencing of the putative MUC18 promoter region revealed a G+C-rich promoter lacking conventional TATA and CAAT boxes. Several motifs for binding of transcription factor Sp1 are pre sent in the regulatory region, and only a single transcription start s ite within a presumed initiator sequence was identified. Sequence elem ents which might confer melanocyte-specific expression were not detect ed. Instead, recognition sequences for the transcription factors CREB, AP-2, and c-Myb, as well as CArG-box motifs, were observed. These ele ments may contribute to the differential regulation of the MUC18 gene in normal and malignant tissues and suggest a role for this putative a dhesion molecule in neural crest cells during embryonic development.