The POU domain transcription factor Brn-2: elevated expression in malignant melanoma and regulation of melanocyte-specific gene expression.
Previous work has shown that melanoma cell lines express a distinct octamer binding protein. Given the role of octamer-binding proteins in cell differentiation and development, the role this factor is a key issue in understanding melanocyte differentiation and transformation. Using a proteolytic clipping assay, we show that the melanoma-specific octamer factor is Brn-2/N-Oct3, a POU domain protein previously known to be expressed in adult brain and in the developing nervous system. N-Oct3 mRNA was detected in a range of human melanoma cell lines and was around 10-fold elevated compared to normal human melanocytes while mRNA for Brn-2 was also detected in a mouse melanoblast cell line. Expression of Brn-2/N-Oct3, in melanoma cells in cotransfection assays activated the expression of the MHC class II DR alpha promoter but repressed the activity of the melanocyte-specific tyrosinase promoter. Repression correlated with Brn-2/N-Oct3 binding in a mutually exclusive fashion with basic-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor USF in vitro and with Brn-2 expression preventing activation of the tyrosinase promoter by the bHLH-LZ factor Microphthalmia in vivo. The potential role of Brn-2/N-Oct3 in melanocyte differentiation and gene expression is discussed.
D000951:Antigens, Neoplasm; D001483:Base Sequence; D001665:Binding Sites; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006684:HLA-DR Antigens / Q000235:genetics; D018257:Helix-Loop-Helix Motifs / Q000502:physiology; D018398:Homeodomain Proteins; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D058950:Melanoma-Specific Antigens; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050809:POU Domain Factors; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; D006684:HLA-DR Antigens; D018398:Homeodomain Proteins; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D050809:POU Domain Factors; D012333:RNA, Messenger; D014157:Transcription Factors; C085076:transcription factor Brn-2; D014442:Monophenol Monooxygenase