Mol Cell Biol, April 1998, p. 2108-2117, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Gene in Hepatocytes Is Mediated by Stat3 and Sp1
Eukaryotic Transcriptional Regulation Group, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201
Received 15 July 1997/Returned for modification 3 September 1997/Accepted 9 January 1998
C/EBP
(CCAAT/enhancer binding protein
) has been implicated
as a regulator of acute-phase response (APR) genes in hepatocytes. Its
expression increases dramatically in liver during the APR and can be
induced in hepatic cell lines by interleukin-6 (IL-6), an acute-phase
mediator that activates transcription of many APR genes. Here we have
investigated the mechanism by which C/EBP
expression is regulated by
IL-6 in hepatoma cells. C/EBP
promoter sequences to
125 bp are
sufficient for IL-6 inducibility of a reporter gene and include an APR
element (APRE) that is essential for IL-6 responsiveness. DNA binding
experiments and transactivation assays demonstrate that Stat3, but not
Stat1, interacts with this APRE. Two Sp1 sites, one of which is
adjacent to the APRE, are required for IL-6 induction and
transactivation by Stat3. Thus, Stat3 and Sp1 function cooperatively to
activate the C/EBP
promoter. Replacement of the APRE with Stat
binding elements (SBEs) from the ICAM-1 or C/EBP
promoter, both of
which recognize both Stat1 and Stat3, confers responsiveness to gamma
interferon, a cytokine that selectively activates Stat1. Sequence
comparisons suggest that the distinct Stat binding specificities of the
C/EBP
and C/EBP
SBEs are determined primarily by a single base
pair difference. Our findings indicate that the cytokine specificity of
C/EBP
gene expression is governed by the APRE sequence.
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