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A 3'-Transcribed Region of the HLA-A2 Gene Mediates Posttranscriptional Stimulation by IFN-¹

Steven R. Snyder^2,*,, Jeffrey F. Waring^2,3,, Sheng Zu Zhu^*, Sarah Kaplan^*, Julie Schultz^*, and Gordon D. Ginder^4,*,,

^* Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and Institute of Human Genetics and Department of Medicine, University of Minnesota, Minneapolis, MN 55455

The expression of several MHC class I genes is up-regulated at the transcriptional level by IFN-. Posttranscriptional mechanisms also have been implicated, but not well characterized. To investigate the mechanism of IFN- stimulation of the human MHC class I gene HLA-A2, several human tumor cell lines were transfected with reporter gene constructs driven by the HLA-A2 promoter. We have previously shown that the extended 525-bp HLA-A2 promoter alone, which includes a 5' IFN-stimulated response element consensus sequence, is not sufficient for IFN- response in either K562 or Jurkat cells. In the current study, stable transfection of a genomic HLA-A2 gene construct, containing both 5'- and 3'-flanking sequences, resulted in stimulation of the gene by IFN-. Nuclear run-on assays revealed that, unlike other class I genes, IFN- stimulation of HLA-A mRNA accumulation occurs almost entirely through posttranscriptional mechanisms. RNA stability assays showed that the effect is not mediated by alteration of the half-life of the HLA-A2 mRNA. Formation of the 3' end was unaffected by IFN- treatment. Sequences that mediate the majority of IFN- induction of HLA-A2 mRNA reside in a 127-bp 3'-transcribed region of the gene. This region contains the terminal splice site, the usage of which is not affected by IFN- treatment. These results demonstrate a novel posttranscriptional mechanism of regulation of MHC class I genes by IFN-.

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