SPI-C is a novel ETS protein that is expressed in B lymphocytes. No target gene for SPI-C has so far been defined. We have performed a yeast two-hybrid screen using SPI-C as bait in order to further analyze the functional role of this orphan transcription factor. We found that SPI-C interacted specifically with the C-terminus of STAT6 in yeast. By co-immunoprecipitation in transfected COS7 cells the physical interaction between SPI-C and STAT6 was confirmed. Furthermore, this protein-protein interaction is functional since we could demonstrate that SPI-C and STAT6 stimulated IL4 induced 1 epsilon transcription synergistically but only when both proteins bound to DNA. Thus, a protein interaction between SPI-C and STAT6 is the basis for a novel mechanism for regulation of IL4 induced gene expression. (c) 2006 Elsevier Inc. All rights reserved.