MULTIPLE LEVELS OF MHC CLASS-I DOWN-REGULATION BY RAS ONCOGENES

A number of tumours and oncogene transformed cells displayed reduced M HC class I surface expression which seemed to enable their escape from immune surveillance. To test whether oncogenic activation is directly involved in suppressing MHC class I expression, a model of inducible oncogene expression was chosen. Mouse fibroblasts transfected with dif ferent oncogenes expressed under the control of the dexamethasone-indu cible MMTV promoter were analysed in the presence and absence of hormo ne for the mRNA and protein expression of MHC class I molecules as wel l as the respective oncogenes, Immunofluorescence analyses demonstrate d an inverse association of MHC class I and oncogene expression after dexamethasone stimulation, independent of the type of oncogene causing transformation. Hormone-mediated induction of oncogene expression cau sed down-regulation of all H-2 loci. Kinetic experiments using MMTV c- Ha-ras(A) transfectants revealed that down-regulation of MHC class I s urface expression was preceded by a dexamethasone-induced change of mo rphology, anchorage-independent growth, and an increase of the ras pro tein p 21. Parallel monitoring of mRNA expression demonstrated a time- dependent up-regulation of ras specific transcripts, which was associa ted with differential regulation of MHC class I heavy and light chain transcripts. beta(2)-microglobulin transcripts were transiently suppre ssed, whereas MHC class I heavy chain transcripts remained unaffected. To investigate the mechanisms of oncogene-mediated down-regulation of MHC class I expression, H-2 promoter transfections and a nuclear run on assays were performed, In MMTV c-Ha-ras(A) cells, neither alteratio ns of the H-2 promoter activity nor of the transcriptional activity of H-2 antigens was observed in the presence of dexamethasone, whereas b oth could be up-regulated by interferon-gamma treatment. These data su ggest that oncogene-mediated transformation is directly associated wit h MHC class I down-regulation, but that complex interactions affecting MHC class I heavy and light chain genes at the transcriptional and/or post-transcriptional level are involved in this process.