Cis-acting elements determine the locus-specific shutoff of class I major histocompatibility genes in murine S49 lymphoma sublines.
Several tumors have been reported to down-regulate expression of their class I major histocompatibility molecules, potentially altering their immune recognition. To investigate this phenomenon, we are using various sublines isolated from the S49 lymphoma of the BALB/c mouse strain. These S49 tumor sublines were previously found to have shut off expression of their Kd, Dd, and/or Ld class I molecules in a locus-specific manner. Extensive Southern blot analyses indicated that there were no major chromosome aberrancies in these S49 sublines, and analyses of steady-state class I mRNA suggested that a form of transcriptional regulation was responsible for their variant class I expression. In this report, we characterize the nature of this locus-specific regulation of class I in S49 cells by producing somatic cell hybrids. Three phenotypically distinct S49 sublines were each fused to tumor cells with normal class I expression, and several of the resulting hybrids were analyzed. In every case, the class I molecules expressed by the hybrids were an exact composite of the two fusion partners. Thus, these fusions failed to rescue expression of the Kd, Dd, and/or Ld molecules shut off within each of the S49 tumor sublines. These findings indicate that this locus-specific shutoff of class I expression results from a cis-acting defect and not trans-acting factors. Because the analysis of each of three phenotypically different S49 cells implicated a form of cis-dominant regulation, we hypothesize that a common mechanism generating homologous mutations in class I genes is operative in S49 tumor cells.
Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110.
J B
JB
Keeney
T H
TH
Hansen
D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D005809:Genes, Regulator; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000235:genetics; D006822:Hybrid Cells / Q000276:immunology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C
D015395:Histocompatibility Antigens Class I