C-MYC REPRESSES TRANSIENTLY TRANSFECTED HLA CLASS-I PROMOTER SEQUENCES NOT LOCUS-SPECIFICALLY

Overexpression of the c-myc oncogene is frequently accompanied by down regulation of Major Histocompatibility Complex (MHC, HLA in humans) cl ass I antigens. In human melanoma c-myc overexpression downmodulates H LA-B expression, whereas HLA-A is hardly affected. Repression of HLA-B is mediated through the core promoter, containing a CAAT-box and a no n-conventional TATA-box. We show evidence that in transient transfecti on assays the HLA-A2 and HLA-B7 promoters are repressed by c-myc to ch e same extent. Therefore, other sequences of the HLA-A and HLA-B genes , possibly intron/exon sequences, should contribute to the locus B-spe cificity of the downregulation. Furthermore, c-myc does not seem to al ter binding of protein complexes to the CAAT- or TATA-box of HLA-B7 or HLA-A2 in gel retardation assays. Comparison of promoters repressed b y c-myc reveals a weak consensus sequence of the initiator (Inr) eleme nt: TCA(+1)YYYNY. The presence of a TCA sequence in the initiator regi on of the MHC class I promoter makes downregulation by c-myc through t he Inr likely. We speculate that the Inr contributes to MHC class I pr omoter activity by stimulating recruitment of TFIID to the weak, non-c onventional TATA-box, thereby making it susceptible to repression by c -myc through the Inr.