Abstract
Both constitutive and interferon-inducible enhancer-like elements have been identified previously in the promoter of human leukocyte antigen (HLA) class I genes. One of these sites is termed the interferon-stimulated response element (ISRE). We have tested the function of an ISRE consensus sequence in the human HLA class I gene HLA-A2 and confirmed previous studies that showed that the HLA-A2 ISRE consensus sequence does not mediate a response to interferons. However, deletion of the ISRE consensus sequence caused a several-fold reduction in the constitutive expression of the HLA-A2 gene in K562 and Jurkat cells. Mobility shift assays performed with the HLA-A2 ISRE revealed the presence of a constitutive binding protein (ISRE/CBP). This protein binds specifically to the HLA-A2 ISRE sequence, and binding is not efficiently competed by the ISRE sequences of the HLA-B7 or ISG54 genes. Substitution of the HLA-B7 or ISG54 ISRE sequences for the HLA-A2 ISRE sequence caused a severalfold reduction in the constitutive expression of the HLA-A2 gene. Mass determinations showed the ISRE/CBP to be 105 kDa, different than any previously characterized ISRE binding proteins. We propose that ISRE/CBP is a novel positive transcriptional regulatory factor for the HLA-A2 gene that may contribute to the differential expression of HLA-A versus HLA-B genes.
Highlights
From the +Department of Medicine, Division of Medical Oncology, and the §Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455 and the 'IIGenetics Ph.D
To investigate the potential role of the interferon-stimulated response element (ISRE) in the IFN-y response of the human leukocyte antigen (HLA)-A2 gene, a construct consisting of the HLA-A2 promoter and 525 base pairs of 5'flanking sequence linked to the CAT gene was transfected into both untreated and IFN-y-treated K562 and Jurkat cell lines
Deletion of this ISRE-like element in the HLA-A2 gene does cause a significant reduction in constitutive HLA-A2 expression in both K562 and Jurkat cells, as measured by CAT assays and RNase protections
Summary
From the +Department of Medicine, Division of Medical Oncology, and the §Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455 and the 'IIGenetics Ph.D. University of Iowa, Iowa City, Iowa 52242 Both constitutive and interferon-inducible enhancerlike elements have been identified previously in the promoter of human leukocyte antigen (HLA) class I genes. One of these sites is termed the interferon-stimulated response element (ISRE). We have tested the function of an ISRE consensus sequence in the human HLA class I gene HLA-A2 and confirmed previous studies that showed that the HLA-A2 ISRE consensus sequence does not mediate a response to interferons. Mobility shift assays performed with the HLA-A2 ISRE revealed the presence of a constitutive binding protein (ISRE/CBP) This protein binds to the HLA-A2 ISRE sequence, and binding is not efficiently competed by the ISRE sequences of the HLA-B7 or ISG54 genes. Studies of HLA class I locus-specific response to interferon have shown that the different class I subtypes have varying levels of response to both type I and type II interferons (Sanderson and Beverly, 1983; Hakem et al, 1991)
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