NEGATIVE REGULATION BY THE R2 ELEMENT OF THE MHC CLASS-I ENHANCER IN ADENOVIRUS-12 TRANSFORMED-CELLS CORRELATES WITH HIGH-LEVELS OF COUP-TFBINDING

The transcriptional down-regulation of the major histocompatibility co mplex (MHC) class I antigens in adenovirus type 12 (Ad12) transformed cells gives them the potential to escape immunosurveillance and to for m tumors. The enhancer of the class I promoter is the target of transc riptional repression which is mediated by the E1A gene of Ad12. The R2 region within the class I enhancer acts as a negative element in Ad12 -transformed cells and exhibits a stronger binding activity than is ob served in nontumorigenic Ad5-transformed cells, which are not reduced in class I expression. The R2 element contains a nuclear hormone recep tor half-site consensus sequence, AGGTCA, which is required for both t he binding activity and the ability of R2 to act as a negative element in Ad12-transformed cells. In this study, we show that an orphan horm one receptor protein, COUP-TF, contributes to the differential R2 bind ing activity observed between Ad12- and Ad5-transformed cells. Additio nally, COUP-TF was shown to bind as a dimer to the R2 element and to u se the consensus AGGTCA as one half-site and its 3' flanking sequence as a probable second degenerate half-site. Since COUP-TF can act as a transcriptional repressor, we suggest that the higher COUP-TF binding activity to the R2 element in Ad12-transformed cells contributes to do wn-regulation of class I transcription and, consequently, tumorigenesi s.