Specific inhibition of interleukin-4-dependent Stat6 activation by an intracellularly delivered peptide.
The transcription factor Stat6 (signal transducer and activator of transcription 6) is activated following stimulation with interleukin (IL)-4 or IL-13. Stat6 binds via a single SH2 domain first to tyrosine-phosphorylated motifs in the IL-4Ralpha chain, and then to another Stat6 molecule, which results in the formation of active dimers. We show here that a peptide derived from the Stat6-binding region of IL-4Ralpha (Stat6BP) is an effective inhibitor when it is delivered into cells by coupling with a membrane-permeable peptide. Stat6BP completely inhibited IL-4 dependent phosphorylation of Stat6, as well as basal and IL-4 stimulated transcription from a reporter gene construct with a Stat6-dependent promoter, while IL-3 and IL-4 dependent phosphorylation of Stat5 was not affected. The inhibitory effect of Stat6BP was transient, but could be prolonged by treating the cells with the phosphatase inhibitor pervanadate.
Stolzenberger
S
S
Biocenter, Physiological Chemistry II, Würzburg, Germany.
Haake
M
M
Duschl
A
A
D051943:Antennapedia Homeodomain Protein; D002463:Cell Membrane Permeability; D004268:DNA-Binding Proteins / Q000378:metabolism; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D008894:Milk Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019948:Receptors, Interleukin-4 / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology
D051943:Antennapedia Homeodomain Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D008894:Milk Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C076715:pervanadate; D015847:Interleukin-4; D014638:Vanadates