STAT6 and Ets-1 form a stable complex that modulates Socs-1 expression by interleukin-4 in keratinocytes

J Biol Chem. 2004 Aug 20;279(34):35183-92. doi: 10.1074/jbc.M403223200. Epub 2004 Jun 15.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism*
  • Interleukin-4 / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Keratinocytes / metabolism*
  • Molecular Sequence Data
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • STAT6 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • ETS1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Interleukin-4