Paired Stat6 C-terminal transcription activation domains required both for inhibition of an IFN-responsive promoter and trans-activation.

Goenka S, Youn J, Dzurek LM, Schindler U, Yu-Lee LY, Boothby M
J Immunol. 1999 163 (9): 4663-72

PMID: 10528163

The cytokines IL-4 and IFN-gamma exert biologically antagonistic effects that in part reflect opposing influences on gene transcription. While the molecular mechanisms for IL-4-mediated transcription activation have been extensively studied, little is known about molecular mechanisms required for IL-4 inhibition of IFN-gamma signaling. We have investigated IL-4 inhibition of the IFN-gamma-inducible promoter for IFN regulatory factor-1 (IRF-1). In a cell line with low endogenous Stat6, increasing levels of activated Stat6 at constant doses of IFN-gamma and IL-4 leads to inhibition of the IRF-1 promoter. The Stat1-dependent IFN-gamma activation sequence element of the IRF-1 promoter is a target for Stat6-mediated inhibition despite apparently normal Stat1 DNA binding. However, our data are inconsistent with competition between Stat1 and Stat6 for access to the IRF-1 IFN-gamma activation sequence or for an essential coactivator as a mechanism for this Stat6-mediated inhibition. Instead, the data demonstrate that a threshold of Stat6 transcription activation domains is required for IL-4-dependent inhibition. The findings provide evidence of a novel mechanism in which the Stat6 transcription activation domains play a critical role in the IL-4-mediated inhibition of an IFN-gamma-inducible promoter.

MeSH Terms (18)

Binding, Competitive Cell Line Cell Nucleus DNA-Binding Proteins Humans Interferon-gamma Interferon Regulatory Factor-1 Interleukin-4 Peptide Fragments Phosphoproteins Promoter Regions, Genetic Protein Binding Regulatory Sequences, Nucleic Acid Signal Transduction STAT6 Transcription Factor Trans-Activators Transcriptional Activation Tumor Cells, Cultured

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