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Query: UNIPROT:P42226 (Signal transducer and activator of transcription 6)
 35 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transducer and activator of transcription 6 (Stat6) has a crucial role in regulation of IL-4-induced gene responses. Stat6-binding sites are present in the promoters of both ubiquitously and cell-type-specifically expressed genes. The promoter regions of IL-4-inducible genes contain cis-acting elements for several transcription factors that act in concert with Stat6 and are also likely to modulate lineage-specific gene expression. We have observed that the Stat6 response element from the B-cell-specific Igepsilon promoter is readily activated upon IL-4 stimulation in B cells but not in non-hematopoietic cells. A minimal low-affinity PU.1-core-binding sequence (5'-AGAA-3') was identified within the Stat6 DNA-binding site in the Igepsilon promoter. Ectopic expression of the myeloid- and B-cell-specific transcription factor PU.1 restored the IL-4-inducibility of the Igepsilon-Stat6 response element in HepG2 cells, and the induction required an intact PU.1-binding sequence. Both the transactivation and the DNA-binding domains of PU.1 were required for induction of Stat6-mediated transcription. The co-operation between PU.1 and Stat6 in transactivation of the Igepsilon gene represents a molecular mechanism for the fine-tuning of cell-type-restricted expression of IL-4-induced gene responses.
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PMID:PU.1 is required for transcriptional activation of the Stat6 response element in the Igepsilon promoter. 1277 91

Signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 (IL-4) by direct interaction with coactivators. The CREB-binding protein (p300/CBP) and the nuclear coactivator 1 (NCoA-1), a member of the p160/steroid receptor coactivator family, bind independently to specific regions of the STAT6 transactivation domain and act as coactivators. The interaction between STAT6 and NCoA-1 is mediated by an LXXLL motif in the transactivation domain of STAT6. To define the mechanism of coactivator recognition, we determined the crystal structure of the NCoA-1 PAS-B domain in complex with the STAT6 LXXLL motif. The amphipathic, alpha-helical STAT6 LXXLL motif binds mostly through specific hydrophobic interactions to NCoA-1. A single amino acid of the NCoA-1 PAS-B domain establishes hydrophilic interactions with the STAT6 peptide. STAT6 interacts only with the PAS-B domain of NCoA-1 but not with the homologous regions of NCoA-2 and NCoA-3. The residues involved in binding the STAT6 peptide are strongly conserved between the different NCoA family members. Therefore surface complementarity between the hydrophobic faces of the STAT6 fragment and of the NCoA-1 PAS-B domain almost exclusively defines the binding specificity between the two proteins.
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PMID:Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. 1475 47

Signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 (IL-4) by direct interaction with coactivators. Among them, NCoA-1, a member of the p160/steroid receptor coactivator (SRC) family, has been found to bind to STAT6 with the region B of its putative Per-Arnt-Sim (PAS) domain. STAT6 interacts specifically with NCoA-1 via an LXXLL motif in its transactivation domain. Crystals of the NCoA-1(257-385) domain in complex with the STAT6(794-814) LXXLL motif were obtained in two hexagonal space groups. The crystals in space group P6(1), with unit-cell parameters a = 61.7, b = 61.7, c = 146.5 A, alpha = beta = 90, gamma = 120 degrees, diffract to 2.8 A at a home source. Crystals belonging to space group P6(2), with unit-cell parameters a = 62.0, b = 62.0, c = 73.6 A, alpha = beta = 90, gamma = 120 degrees, diffract to 1.8 A at a synchrotron source.
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PMID:Crystallization and preliminary crystallographic studies of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. 1499 89

Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-kappaB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.
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PMID:Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. 1499 88

Signal transducer and activator of transcription 6 is a transcription factor important for the development of Th2 cells and regulation of gene expression by IL-4 and IL-13. It has been reported that STAT1 activity is regulated by methylation of a conserved arginine residue in the N-terminal domain. Methylation of STAT6 has not yet been explored. We observed methylation of STAT6 in cells transfected with wild-type STAT6, but not in cells transfected with Arg(27)Ala mutant, confirming that STAT6 is methylated on Arg(27). Transfectants expressing mutant Arg(27)Ala STAT6 displayed markedly diminished IL-4-dependent STAT6 phosphorylation and nuclear translocation, and no STAT6 DNA-binding activity compared with wild-type STAT6 transfectants. To confirm this, the experiments were repeated using inhibitors of methylation. In the presence of methylation inhibitors, STAT6 methylation was diminished, as was phosphorylation of STAT6 and STAT6 DNA-binding activity. Thus, methylation is a critical regulator of STAT6 activity, necessary for optimal STAT6 phosphorylation, nuclear translocation, and DNA-binding activity. Furthermore, methylation of STAT6 has distinct effects from those reported with STAT1.
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PMID:Methylation of STAT6 modulates STAT6 phosphorylation, nuclear translocation, and DNA-binding activity. 1515 91

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impulsiveness and inattention that begins in childhood. The underlying pathogenesis of this disorder is still unknown, although pharmacological, genetic and neuroimaging studies suggest that dopamine transportation may be implicated in the pathogenesis of ADHD. Signal transducer and activator of transcription 6 (STAT6), similar to other members of the signal transducer and activator of transcription family of proteins, is an important molecule in the induction and regulation of the immune response. Animal studies have demonstrated that STAT6 is highly expressed in the CNS, especially in the developing brain. Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type. From these findings, and evidence from other studies, it can be proposed that STAT6 may be implicated in the pathogenesis of ADHD. Several proposals to test this hypothesis are suggested; attempts to prove the STAT6-ADHD hypothesis may provide a new direction that elucidates the pathogenesis of and a treatment for ADHD.
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PMID:Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: a speculative hypothesis. 1684 17

Signal transducer and activator of transcription 6 (STAT6) is a regulator of transcription for interleukin-4 (IL-4)-induced genes. The ability of STAT6 to activate transcription depends on functional interaction with other transcription factors and coactivators. We have characterized the mechanism of STAT6-mediated transcriptional activation by identifying STAT6 transcription activation domain (TAD) interacting nuclear proteins. The first of the identified proteins was coactivator protein p100, which regulates IL-4-induced transcription by connecting STAT6 with other transcriptional regulators. Here, we describe RNA helicase A (RHA) as a novel component of STAT6 transcriptosome. In vitro and in vivo experiments indicated that RHA did not directly interact with STAT6, but p100 protein was found to mediate the assembly of the ternary complex of STAT6-p100-RHA. In chromatin immunoprecipitation studies RHA together with p100 enhanced the binding of STAT6 on the human Igepsilon promoter after IL-4 stimulation. RHA enhanced the IL-4-induced transcription, and the participation of RHA in IL-4-regulated transcription was supported by RNAi experiments. Our results suggest that RHA has an important role in the assembly of STAT6 transcriptosome. As RHA is also known to interact with chromatin modifying proteins, the RHA containing protein complexes may facilitate the entry of transcriptional apparatus to the IL-4 responsive promoters.
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PMID:Characterization of RNA helicase A as component of STAT6-dependent enhanceosome. 1691 50

Signal transducer and activator of transcription 6 (STAT6) is critical for IL-4 and IL-13 responses, and necessary for the normal development of Th2 cells. We previously generated mice that express a constitutively active STAT6 (STAT6VT) under control of the CD2 locus control region, which directs expression to the T-cell compartment. We now describe that a small proportion of these mice (~5%) develop a spontaneous lymphoproliferative disease (LPD) that results in dramatic splenomegaly. The cell populations observed in the LPD spleens can be divided into 2 categories, those that are composed of mixed lineage cells and those that are predominantly T cells with a phenotype similar to that in autoimmune lymphoproliferative syndrome (ALPS) patients. These data suggest that while active STAT6 is not a transforming factor, expression in T cells predisposes toward the development of lymphoproliferative disorders.
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PMID:Constitutively active STAT6 predisposes toward a lymphoproliferative disorder. 1787 3

Signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a central role in asthma pathogenesis, with its activation driving the development of airway hyper-reactivity and local inflammation. Therefore, inhibition of local STAT6 expression provides a rationale for therapeutic intervention in bronchial asthma. Given the absence of specific inhibitory drugs, we tested the ability of small interfering RNAs (siRNAs) to target STAT6 gene expression through the molecular process of RNA interference (RNAi). At pico-molar concentrations, STAT6-specific siRNAs potently inhibited STAT6 mRNA expression in lung epithelial cells (50% inhibitory concentration range = 134-861 pm) without inducing cellular interferon responses. Detectable STAT6 protein expression was rapidly abolished within 48 hr of treatment (t(1/2) range = or < 12-37 hr) and this was unaffected by pretreatment with STAT6-activating cytokines. Furthermore, STAT6 suppression by RNAi produced downstream functional inhibitory effects in that interleukin (IL)-13- or IL-4-driven eotaxin chemokine family [chemokine (C-C motif) ligand 11 (CCL11), CCL24 and CCL26] mRNA expression was markedly inhibited. Induction of detectable CCL26 protein synthesis was completely ablated by pretreating cells with STAT6-specific siRNA. The therapeutic potential of this approach is further demonstrated by novel findings that cells pre-exposed to IL-13 or IL-4 and subsequently treated with STAT6-targeting siRNA exhibited a rapid and significant attenuation of ongoing CCL26 protein expression, suggesting that chronic asthma-associated lung inflammation will be responsive to this approach.
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PMID:RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells. 1917 98

Identification of the genes and polymorphisms underlying quantitative traits, and understanding how these genes and polymorphisms affect economic traits, are important for successful marker-assisted selection and more efficient management strategies in commercial cattle populations. Signal transducer and activator of transcription 6 (STAT6) gene is tightly connected to IL-4 and IL-13 signalling and plays a key role in T(H)2 polarization of the immune system. In addition, STAT6 acts as a mediator of leptin signalling and has been associated with body weight regulation. The objective of this study was to determine if SNPs within the bovine STAT6 gene are associated with economically important traits in feedlot cattle. The approach consisted of resequencing STAT6 using a panel of DNA from unrelated animals of different beef breeds. Specifically, 16 kb of STAT6 was resequenced in 47 animals and the process revealed 39 SNPs. From the 39 SNPs, a panel of 15 tag SNPs was genotyped in 1500 beef cattle samples with phenotypes to perform a marker-trait association analysis. Among the 15 tag SNPs, five and six were polymorphic in Bos taurus and Bos indicus respectively. An association analysis was performed between the 15 tag SNPs and 14 performance and production traits. SNP ss115492459:C > A, ss115492461:A > G and ss115492458:G > C were significantly associated with back fat, calculated yield grade, cutability, hot carcass weight, dry matter intake, days on feed, back fat rate and average daily gain. These three SNPs were present in all Bos taurus beef breeds examined. Our results provide evidence that polymorphisms in STAT6 are associated with carcass and growth efficiency traits, and may be used for marker-assisted selection and management in feedlot cattle.
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PMID:Polymorphisms in the STAT6 gene and their association with carcass traits in feedlot cattle. 1951 91


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