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PMID: 9528783 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Interleukin-6-specific activation of the C/EBPdelta gene in hepatocytes is mediated by Stat3 and Sp1.

Molecular and cellular biology ·Vol. 18 ·No. 4 ·1998-04-00 ·Pages 2108-17

Cantwell CA, Sterneck E, Johnson PF

Abstract

C/EBPdelta (CCAAT/enhancer binding protein delta) 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/EBPdelta expression is regulated by IL-6 in hepatoma cells. C/EBPdelta 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/EBPdelta promoter. Replacement of the APRE with Stat binding elements (SBEs) from the ICAM-1 or C/EBPbeta 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/EBPdelta and C/EBPbeta SBEs are determined primarily by a single base pair difference. Our findings indicate that the cytokine specificity of C/EBPdelta gene expression is governed by the APRE sequence.

MeSH Terms
Acute-Phase Proteins/metabolism Acute-Phase Reaction/genetics Base Sequence CCAAT-Enhancer-Binding Protein-delta CCAAT-Enhancer-Binding Proteins Chromosome Mapping Cloning, Molecular DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation Humans Interleukin-6/physiology Liver/metabolism Molecular Sequence Data Nuclear Proteins/genetics Promoter Regions, Genetic STAT1 Transcription Factor STAT3 Transcription Factor Sp1 Transcription Factor/metabolism Trans-Activators/metabolism Transcription Factors Transcriptional Activation Tumor Cells, Cultured
Chemicals
Acute-Phase Proteins CCAAT-Enhancer-Binding Proteins CEBPD protein, human DNA-Binding Proteins Interleukin-6 Nuclear Proteins STAT1 Transcription Factor STAT1 protein, human STAT3 Transcription Factor STAT3 protein, human Sp1 Transcription Factor Trans-Activators Transcription Factors CCAAT-Enhancer-Binding Protein-delta
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Cantwell C A
Eukaryotic Transcriptional Regulation Group, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Sterneck E
Johnson P F
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.18.4.2108
Published
1998-04-00
Pages
2108-17
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC121443
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.18.4.2108 PMC Full Text View journal details
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