Multiple levels of MHC class I down-regulation by ras oncogenes

Scand J Immunol. 1996 May;43(5):537-44. doi: 10.1046/j.1365-3083.1996.d01-73.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Antigens, Surface / drug effects
  • Dexamethasone / pharmacology
  • Down-Regulation / genetics
  • Gene Expression / drug effects
  • Genes, ras / physiology*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / physiology*
  • Immunoglobulin Heavy Chains / genetics
  • Mammary Tumor Virus, Mouse / genetics
  • Mice
  • Promoter Regions, Genetic
  • RNA Processing, Post-Transcriptional
  • Transcription, Genetic
  • Transfection / drug effects
  • beta 2-Microglobulin / genetics


  • Antigens, Surface
  • Histocompatibility Antigens Class I
  • Immunoglobulin Heavy Chains
  • beta 2-Microglobulin
  • Dexamethasone