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Papers In Press, published online ahead of print July 22, 2002
Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Hessen 60596
Corresponding Author: e.pfitzner{at}em.uni-frankfurt.de
Signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to Interleukin-4 (IL-4)-induced tyrosine phosphorylation by direct interaction with coactivators. The CREB binding protein (CBP) and the nuclear coactivator 1 (NCoA-1), a member of the p160/steroid receptor coactivator (SRC) family, bind independently to specific regions of STAT6 and act as coactivators. In this study we show that a LXXLL motif in the STAT6 transactivation domain mediates the interaction with NCoA-1. Peptides representing this motif as well as antibodies generated against this motif, inhibited STAT6/NCoA-1 interaction in glutathione-S-transferase pulldown assays. Peptides derived from the STAT6 transactivation domain adjacent to the LXXLL motif, as well as antibodies against these peptides showed no inhibitory effect. Mutagenesis of the LXXLL motif eliminated the STAT6/NCoA-1 interaction in vitro and in vivo, supporting the specific role of this motif in NCoA-1 binding. Importantly, mutagenesis of the STAT6 LXXLL motif strongly diminished the IL-4-regulated activation of the endogenous STAT6 target gene eotaxin-3. Taken together, these results indicate that the STAT6-LXXLL-binding motif mediates the interaction with NCoA-1 in transcriptional activation, and represents a new potential drug target for the inhibition of the STAT6 transactivation function in allergic diseases.
J. Biol. Chem, 10.1074/jbc.M203556200
Submitted on April 12, 2002
Revised on July 9, 2002
Accepted on July 19, 2002
A LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1
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