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1
,
*
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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