Transcriptional activation by STAT6 requires the direct interaction with NCoA-1

Signal transducer and activator of transcription 6 (STAT6) is a transcripti on factor that is activated by interleukin-4 (IL-4)-induced tyrosine phosph orylation and mediates most of the IL-4-induced gene expression. Transcript ional activation by STAT6 requires the interaction with coactivators like p 300 and the CREB-binding protein (CBP). In this study we have investigated the function of the CBP-associated members of the p160/ steroid receptor co activator family in the transcriptional activation by STAT6. We found that only one of them, NCoA-1, acts as a coactivator for STAT6 and interacts dir ectly with the transactivation domain of STAT6. The N-terminal part of NCoA -1 interacts with the far C-terminal part of the STAT6 transactivation doma in but does not interact with the other members of the STAT family. This do main of NCoA-1 has a strong inhibitory effect on STAT6-mediated transactiva tion when overexpressed in cells, illustrating the importance of NCoA-1 for STAT6-mediated transactivation. In addition, we showed that both coactivat ors CBP and NCoA-1 bind independently to specific regions within the STAT6 transactivation domain. Our results suggest that multiple contacts between NCoA-1, CBP, and STAT6 are required for transcriptional activation. These f indings provide new mechanistic insights into how STAT6 can recruit coactiv ators required for IL-4-dependent transactivation.