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Multiple Levels of MHC Class I Down‐Regulation by ras Oncogenes
Author(s) -
LOHMANN S.,
WOLLSCHEID U.,
HUBER C.,
SELIGER B.
Publication year - 1996
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.1996.d01-73.x
Subject(s) - mhc class i , oncogene , biology , major histocompatibility complex , microbiology and biotechnology , beta 2 microglobulin , immune system , gene , immunology , cell cycle , genetics
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. β 2 ‐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‐γ 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.