Abstract
Suppressor of cytokine signaling (SOCS)-1 is a critical regulator of lipopolysaccharide (LPS) tolerance and LPS-induced cytokine production. The mechanisms regulating the transcription of SOCS-1 in response to LPS are not entirely understood. Functional analysis of the SOCS-1 promoter demonstrates that early growth response-1 (Egr-1) is an important transcriptional regulator of SOCS-1. Two Egr-1 binding sites are present within the SOCS-1 promoter as shown by EMSA and supershift analysis. Further, mutation of the Egr-1 binding sites significantly reduces both the basal and LPS-induced transcriptional activity of the promoter. Chromatin immunoprecipitation experiments confirm LPS-induced binding of Egr-1 to the SOCS-1 promoter in vivo. Additionally, Egr-1(-/-) macrophages show reduced levels of LPS-induced SOCS-1 expression in comparison with macrophages derived from Egr-1(+/+) littermate controls. These results demonstrate an important role for Egr-1 in regulating both the basal and LPS-induced activity of the SOCS-1 promoter.
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Blotting, Northern
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Cell Line
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Chromatin Immunoprecipitation
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Codon
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DNA-Binding Proteins / physiology*
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Early Growth Response Protein 1
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Gene Expression Regulation
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Humans
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Immediate-Early Proteins / physiology*
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Intracellular Signaling Peptides and Proteins / chemistry
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Lipopolysaccharides / metabolism*
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Luciferases / metabolism
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Macrophages / metabolism
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Mutation
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Plasmids / metabolism
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Promoter Regions, Genetic
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Protein Binding
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RNA, Messenger / metabolism
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Repressor Proteins / biosynthesis*
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Repressor Proteins / chemistry
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Sequence Homology, Nucleic Acid
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors / physiology*
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Transcription, Genetic
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Transgenes
Substances
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Codon
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DNA-Binding Proteins
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EGR1 protein, human
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Early Growth Response Protein 1
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Immediate-Early Proteins
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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RNA, Messenger
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Repressor Proteins
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SOCS1 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors
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Luciferases