title: Multiple levels of MHC class I down-regulation by ras oncogenes.
abstract: A number of tumours and oncogene transformed cells displayed reduced MHC 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 different oncogenes expressed under the control of the dexamethasone-inducible MMTV promoter were analysed in the presence and absence of hormone for the mRNA and protein expression of MHC class I molecules as well as the respective oncogenes. Immunofluorescence analyses demonstrated 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 caused down-regulation of all H-2 loci. Kinetic experiments using MMTV c-Ha-ras(A) transfectants revealed that down-regulation of MHC class I surface expression was preceded by a dexamethasone-induced change of morphology, anchorage-independent growth, and an increase of the ras protein p 21. Parallel monitoring of mRNA expression demonstrated a time-dependent up-regulation of ras specific transcripts, which was associated with differential regulation of MHC class I heavy and light chain transcripts. Beta2-microglobulin transcripts were transiently suppressed, 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 alterations of the H-2 promoter activity nor of the transcriptional activity of H-2 antigens was observed in the presence of dexamethasone, whereas both could be up-regulated by interferon-gamma treatment. These data suggest that oncogene-mediated transformation is directly associated with 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.
authors.affiliation: Johannes Gutenberg-University, Third Department of Internal Medicine, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lohmann
authors.forename: U
authors.initials: U
authors.lastname: Wollscheid
authors.forename: C
authors.initials: C
authors.lastname: Huber
authors.forename: B
authors.initials: B
authors.lastname: Seliger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000954:Antigens, Surface / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D014158:Transcription, Genetic; D014162:Transfection / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D000954:Antigens, Surface; D015395:Histocompatibility Antigens Class I; D007143:Immunoglobulin Heavy Chains; D001613:beta 2-Microglobulin; D003907:Dexamethasone