Abstract
Transcriptional activation by signal transducer and activator of transcription 6 (STAT6) has been shown to require the direct interaction not only with co-activators such as p300 and cAMP-responsive element-binding protein-binding protein (CBP) but also with nuclear co-activator 1, a member of the p160/steroid receptor co-activator family. Among the p160/steroid receptor co-activators, only p/CIP (nuclear co-activator 3) has been shown to be up-regulated by interleukin (IL)-4 in B cells through a STAT-6-dependent mechanism using Gene-Chip analysis. In this study, we have investigated the function of p/CIP in the transcriptional activation by STAT6. We found that p/CIP indirectly interacted with STAT6 via p300, and overexpression of the CBP-interacting domain of p/CIP (p/CIP(947-1084)) prevented the interaction of p/CIP with STAT6 by blocking the binding of p/CIP to p300. Whereas expression of p/CIP(947-1084) resulted in a marked reduction of STAT6-mediated transactivation, overexpression of wild type p/CIP resulted in significant enhancement of it. In addition, p/CIP(947-1084) markedly reduced CD23 expression on B cells stimulated with IL-4, whereas overexpression of wild type p/CIP enhanced it. Chromatin immunoprecipitations demonstrate that IL-4 increases the interaction of p/CIP with the murine immunoglobulin heavy chain germ line epsilon promoter in B cells. These results suggest that p/CIP positively regulates STAT6 transcriptional activation through formation of a STAT6, p300/CBP, and p/CIP complex.
Highlights
signal transducer and activator of transcription 6 (STAT6) [1], a member of the family of signal transducer and activator of transcription (STAT),1 is known to be the common signal transducer of interleukin (IL)-4 receptor ␣ chain and mediates IL-4- and IL-13-induced responses [2, 3]
Among the genes that were found to be up-regulated through a STAT6-dependent mechanism, the present study focuses on the function of p300/cAMP-responsive element-binding protein-binding protein (CBP) co-integrating protein (p/CIP) in transcriptional activation by STAT6. p/CIP, called nuclear receptor co-activator-3 (NCoA-3), ACTR, or AIB1, is known to be one of the p160/SRC co-activator family members (19 –21)
Induction of p/CIP by IL-4 in Splenic B Cells—We have recently demonstrated by GeneChip expression analysis that, among the p160/SRC family members, only p/CIP (NCoA-3) mRNA is up-regulated by IL-4 through a STAT6-dependent mechanism in murine primary B cells [18], whereas NCoA-1 and NCoA-2 mRNA are not up-regulated
Summary
STAT6 [1], a member of the family of signal transducer and activator of transcription (STAT), is known to be the common signal transducer of interleukin (IL)-4 receptor ␣ chain and mediates IL-4- and IL-13-induced responses [2, 3]. Statistical analysis revealed that 31 of 70 known genes were expressed at higher levels, and 39 of 70 genes were expressed at lower levels in B cells from STAT6ϩ/ϩ mice in comparison with B cells from STAT6Ϫ/Ϫ mice This suggests that STAT6 acts as a positive and negative regulator of gene expression in IL-4-mediated gene expression. Among the genes that were found to be up-regulated through a STAT6-dependent mechanism, the present study focuses on the function of p300/cAMP-responsive element-binding protein-binding protein (CBP) co-integrating protein (p/CIP) in transcriptional activation by STAT6. P/CIP (NcoA-3) has been demonstrated to enhance ligand-dependent transcription by several nuclear receptors and other CBP-dependent transcription factors such as STAT1 bound to the GAS promoter [19]. Mediated promoter transactivation, and the interference of p/CIP binding to p300 by expression of the CBP-interacting domain of p/CIP results in a strong down-regulation of IL-4mediated gene transcription. This study suggests that p/CIP functions as a co-activator for STAT6mediated activation of gene transcription through interaction with p300/CBP in a positive feedback loop
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