J. Biol. Chem., Vol. 266, Issue 14, 8765-8770, May, 1991
Induced factor binding to the interferon-stimulated response element. Interferon-alpha and platelet-derived growth factor utilize distinct signaling pathways
GE Hannigan and BR Williams
Research Institute, Hospital for Sick Children, Toronto, Canada.
Interferon-alpha (IFN alpha) and platelet-derived growth factor (PDGF) each
rapidly stimulate binding of nuclear factors from Balb/c 3T3 fibroblasts,
to a 29-base pair regulatory sequence derived from the 5' upstream region
of the murine 2-5A synthetase gene. This regulatory sequence contains a
functional interferon-stimulated response element (ISRE) and also functions
as a PDGF-responsive sequence. We show that IFN alpha induces binding of a
protein of molecular mass 65 kDa to the ISRE. Constitutively expressed
ISRE-binding proteins of 98 and 150 kDa are also demonstrated. Binding of
inducible factors to the ISRE increases significantly within 15 min of IFN
alpha or PDGF treatment. PDGF-induced binding is not mediated by IFN beta.
The protein kinase inhibitors, staurosporine and K252a, block PDGF-induced
ISRE binding and 2-5A synthetase gene expression. IFN alpha-induced ISRE
binding and gene activation are not blocked by these inhibitors. Treatment
of cells with 12-O-tetradecanoyl-13-acetate or dibutyryl cyclic AMP does
not activate ISRE binding factors or 2-5A synthetase gene expression. PDGF
responsiveness of the ISRE in vivo is also sensitive to staurosporine,
indicating that inhibition of a protein kinase activity blocks the PDGF-
specific transcriptional signal. Our data indicate the signal transduction
pathway for IFN alpha-induced, ISRE-dependent transcription is distinct
from the PDGF-induced ISRE response and is likely independent of cyclic
AMP-dependent protein kinase and protein kinase C activities.
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