Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.
LAP/C/EBPbeta is a member of the C/EBP family of transcription factors and contributes to the regulation of the acute phase response in hepatocytes. Here we show that IL-6 controls LAP/C/EBPbeta gene transcription and identify an IL-6 responsive element in the LAP/C/EBPbeta promoter, which contains no STAT3 DNA binding motif. However, luciferase reporter gene assays showed that STAT3 activation through the gp130 signal transducer molecule is involved in mediating IL-6-dependent LAP/C/EBPbeta transcription. Southwestern analysis indicated that IL-6 induces binding of a 68-kDa protein to the recently characterized CRE-like elements in the LAP/C/EBPbeta promoter. Transfection experiments using promoter constructs with mutated CRE-like elements revealed that these sites confer IL-6 responsiveness. Further analysis using STAT1/STAT3 chimeras identified specific domains of the protein that are required for the IL-6-dependent increase in LAP/C/EBPbeta gene transcription. Overexpression of the amino-terminal domain of STAT3 blocked the IL-6-mediated response, suggesting that the STAT3 amino terminus has an important function in IL-6-mediated transcription of the LAP/C/EBPbeta gene. These data lead to a model of how tethering STAT3 to a DNA-bound complex contributes to IL-6-dependent LAP/C/EBPbeta gene transcription. Our analysis describes a new mechanism by which STAT3 controls gene transcription and which has direct implication for the acute phase response in liver cells.
Niehof
M
M
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Streetz
K
K
Rakemann
T
T
Bischoff
S C
SC
Manns
M P
MP
Horn
F
F
Trautwein
C
C
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050796:STAT3 Transcription Factor; D016385:TATA Box; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators