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Volume 271, Number 47, Issue of November 22, 1996 pp. 29813-29821
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Locus-specific Enhancer Activity of the Class I Major Histocompatibility Complex Interferon-responsive Element Is Associated with a -Interferon (IFN)-inducible Factor Distinct from STAT1, p48, and IFN Regulatory Factor-1

(Received for publication, May 20, 1996, and in revised form, July 25, 1996)

From the Department of Immunology, Mayo Clinic-Foundation, Rochester, Minnesota 55905

Recent analyses of the upstream regulatory regions of the class I major histocompatibility complex genes in higher primates provided a generalized structural basis for the differential expression of A- and B-locus gene products in response to specific physiological stimulus. Among the regulatory sequences that differ between the loci is the interferon-responsive element (IRE). While the B-IRE is conserved, the A-IREs have species-specific sequence variation. We previously demonstrated that the B-IRE was an interferon (IFN)-inducible enhancer, whereas none of the A-IREs were functional. In the present study, we examined the biochemical basis for the enhancer activity of the conserved B-IRE and found that this may be attributed to a novel -IFN-inducible factor. This factor accumulated in nuclei of cells within minutes of exposure to -IFN. Its appearance was independent of de novo protein synthesis. However, it was not detected in nuclei of cells treated with herbimycin A, suggesting that its appearance depends on a protein kinase activation pathway. Supershift assays indicated that it was distinct from STAT1, IFN regulatory factor-1, and p48, transcription factors known to bind IRE-like sequences found in regulatory regions of many non-major histocompatibility complex -IFN-responsive genes. Competition assays show that this novel factor bound B-IRE with relatively high affinity, about 100-fold more than that for the A-IRE sequence. This factor was also present in STAT1 and p48 somatic mutants that also exhibited B-IRE enhancer activity in reporter gene bioassays in a manner similar to those seen with wild type cells. These observations indicate the existence of a novel -IFN-dependent transcriptional activation pathway that correlates with the differential enhancer activity of the HLA-B IRE.

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