Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression.
Class I antigens encoded in the major histocompatibility complex (MHC) (HLA in man, H-2 in the mouse) play a key role in the recognition of target cells by cytolytic T lymphocytes. Tumor cells frequently do not express class I MHC molecules, which strongly suggests that down-regulation of the latter facilitates escape of tumor cells from immune surveillance. The expression of class I MHC genes is tightly regulated. An enhancer element, conserved in the promoters of mouse and human MHC genes, has been shown to be important for mouse class I MHC gene expression. At least two related regulatory factors (KBF1 and NF-kappa B) bind to this regulatory element. We have analyzed the binding of these factors in cellular extracts of 23 human tumor cell lines displaying various levels of class I mRNA and surface expression. In this panel, combined deficiency of KBF1- and NF-kappa B-like DNA-binding activities was frequent among the class I-negative cell lines and correlated with the absence of class I mRNA. A few cell lines that lack KBF1 binding activity still display NF-kappa B-like activity and express normal levels of MHC class I mRNA. These results suggest (i) that, in the absence of KBF1, NF-kappa B or a related factor promotes MHC class I gene transcription; and (ii) that a combined defect in KBF1/NF-kappa B DNA-binding activity can cause a pleiotropic defect in class I gene expression, which may facilitate tumor progression.
Blanchet
O
O
Institut National de la Santé et de la Recherche Médicale Unité 93, Hôpital Saint-Louis, Paris, France.
Bourge
J F
JF
Zinszner
H
H
Israel
A
A
Kourilsky
P
P
Dausset
J
J
Degos
L
L
Paul
P
P
D000911:Antibodies, Monoclonal; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005260:Female; D015870:Gene Expression; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D015345:Oligonucleotide Probes; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015342:DNA Probes; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D014157:Transcription Factors