TRANSCRIPTIONAL SUPPRESSION OF HLA-B EXPRESSION BY C-MYC IS MEDIATED THROUGH THE CORE PROMOTER ELEMENTS

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 a ffected by c-Myc, is downmodulated at the level of initiation of trans cription. The transcriptional activity of various HLA-B reporter const ructs was tested in a melanoma cell line with low endogenous c-myc exp ression and in transfectants with high stable and transient c-myc expr ession. We demonstrated that the responsive region can be mapped to th e 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 su bject to downregulation is confined to a 43 base pair fragment encompa ssing the CCAAT and TATA elements. By coupling this region to a hetero logous viral enhancer, we showed that the downmodulation by c-Myc is i ndependent of the presence and nature of an enhancer. These results su ggest a mechanism in which c-Myc downregulates the expression of HLA c lass I genes by interfering with the basal level of transcription.