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Regulation of intercellular adhesion molecule-1 gene expression involves
multiple mRNA stabilization mechanisms: effects of interferon- gamma and
phorbol myristate acetate
M Ohh, CA Smith, C Carpenito and F Takei
Department of Medical Genetics, University of British Columbia, Vancouver,
Canada.
Although the intercellular adhesion molecule-1 (ICAM-1) is constitutively
expressed at a low level on a subpopulation of hematopoietic cells, on
vascular endothelium, on fibroblasts, and on certain epithelial cells, it
is dramatically increased at sites of inflammation. Interferon-gamma
(IFN-gamma) and phorbol myristate acetate (PMA) are known to increase the
expression of ICAM-1 on many cell types. Because both human and murine
ICAM-1 mRNAs contain putative destabilizing AUUUA sequences in their 3'
untranslated regions (UTRs), we examined the role of mRNA stability in the
regulation of ICAM-1 gene expression. The treatment of the murine monocytic
cell line P388D1, which constitutively expresses ICAM-1 mRNA at a low
level, with IFN- gamma or PMA rapidly enhanced the level of ICAM-1 mRNA and
dramatically prolonged its half-life. To determine whether the putative
destabilizing sequences are responsible for this effect of IFN-gamma and
PMA, fibroblast L cells were transfected with either the full- length
ICAM-1 cDNA or a truncated form (ICAM-1 delta 3) lacking the putative
destabilizing AUUUA sequences. Although ICAM-1 delta 3 mRNA was more stable
than the full-length ICAM-1 mRNA, IFN-gamma treatment induced the
accumulation of both mRNA species and prolongation of their half-lives. The
transplantation of the ICAM-1 delta 3' UTR into a stable ICAM-2 mRNA
rendered it unstable, and it was unresponsive to IFN- gamma. Therefore, the
treatment with IFN-gamma stabilizes the otherwise labile ICAM-1 mRNA, but
the IFN-gamma-responsive sequence may at least in part reside within the
protein coding region. PMA also upregulated ICAM-1 gene expression by mRNA
stabilization. However, unlike IFN- gamma, PMA treatment only increased the
level of the full-length, but not of the truncated, ICAM-1 mRNA. This shows
that the PMA-responsive element is located within the 3'UTR. Furthermore,
the effect of PMA on ICAM-1 delta 3 mRNA was recovered by ligating multiple
AUUUA sequences derived from a heterologous gene fragment. The stability of
this chimeric mRNA and the full-length ICAM-1 mRNA was markedly increased
by PMA treatment, indicating that the AUUUA multimers in the 3'UTR are
important in the PMA-induced upregulation of ICAM-1 mRNA.
Volume 84,
Issue 8,
pp. 2632-2639,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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