Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements

• Published in: Immunogenetics (New York) 1994-01, Vol.40 (1), p.54-61
• Main Authors: PELTENBURG, L. T. C, SCHRIER, P. L
• Format: Article
• Language: English
• Subjects: Antigens; Base Sequence; Biological and medical sciences; DNA Mutational Analysis; Down-Regulation; Enhancer Elements, Genetic - genetics; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation, Neoplastic; Histocompatibility antigens (hla, h-2 and other systems); HLA-B Antigens - biosynthesis; HLA-B Antigens - genetics; Humans; Melanoma - genetics; Molecular immunology; Molecular Sequence Data; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Regulatory Sequences, Nucleic Acid - genetics; Sequence Homology, Nucleic Acid; Suppression, Genetic; Transcription, Genetic; Transfection; Tumor Cells, Cultured
• ISSN: 0093-7711; 1432-1211
• DOI: 10.1007/BF00163964

In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. This suppression has severe consequences for the recognition of these tumor cells by the immune system of the organism. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. The transcriptional activity of various HLA-B reporter constructs was tested in a melanoma cell line with low endogenous c-myc expression and in transfectants with high stable and transient c-myc expression. We demonstrated that the responsive region can be mapped to the core promoter region of HLA class I, ruling out any effects of c-myc overexpression on the enhancer A or enhancer B regions. The region subject to downregulation is confined to a 43 base pair fragment encompassing the CCAAT and TATA elements. By coupling this region to a heterologous viral enhancer, we showed that the downmodulation by c-Myc is independent of the presence and nature of an enhancer. These results suggest a mechanism in which c-Myc downregulates the expression of HLA class I genes by interfering with the basal level of transcription.