Abstract
Supressor of cytokine signaling (SOCS)-1 is selectively and rapidly induced by appropriate agonists and modulates cytokine responses by interfering with the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. On the basis of the observation that interleukin (IL)-4 up-regulates Socs-1 in the keratinocyte HaCaT cell line, we investigated which sequences of the 5'-Socs-1 gene are responsive to IL-4. We therefore have cloned the 5'-flanking region of this gene, and by promoter analysis we identified a functional IL-4-responsive element located at nucleotide (-684/-570) upstream from the transcription initiation site, whose presence and integrity are necessary to ensure IL-4 responsiveness. This element contains three STAT6 and one Ets consensus binding sequences of which specific mutations abolished IL-4 responsiveness either partially or totally. We also report that Ets-1 physically interacted with STAT6. Exogenous expression of Ets-1 in conjunction with STAT6 activation strongly inhibited expression of a Socs-1 promoter-luciferase reporter. Collectively, our data demonstrated the involvement of STAT6 and Ets, via a composite DNA element, in the IL-4 regulation of Socs-1 gene expression in keratinocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Cell Line
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Gene Expression Regulation
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Humans
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Interleukin-4 / genetics
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Interleukin-4 / metabolism*
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Interleukin-4 / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Keratinocytes / metabolism*
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Molecular Sequence Data
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Phosphorylation
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ets
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Repressor Proteins / biosynthesis*
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Repressor Proteins / genetics
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STAT6 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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ETS1 protein, human
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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Repressor Proteins
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SOCS1 protein, human
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STAT6 Transcription Factor
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STAT6 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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Trans-Activators
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Transcription Factors
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Interleukin-4