B Cell Antigen Receptor Signaling Enhances IFN-γ-Induced Stat1 Target Gene Expression Through Calcium Mobilization and Activation of Multiple Serine Kinase Pathways

Xu, Weifeng; Nair, Jayasree S.; Malhotra, Ajay; Zhang, J Jillian

doi:10.1089/jir.2005.25.113

Cited by 18 publications

(13 citation statements)

References 49 publications

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“…53 Notably, BCR signaling enhances the IFN-c-induced phosphorylation of STAT-1 on serine 727 through calcium mobilization and activation of multiple serine kinase pathways, such as PKC and p38. 54 In the present study, we found that the ligation of CD180 inhibited IFN-a-induced tyrosine phosphorylation of STAT-2, while it had no effect on the IFN-a-induced phosphorylation of JAK1 and STAT-1. We propose that this discrepancy may be attributed to the differences between CD180 signaling and BCR signaling.…”

Section: Discussionsupporting

confidence: 43%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-a (IFN-a) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-a signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-a signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138 1 plasmablast/plasma cells and GL-7 1 germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-a-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-a-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-a signaling in SLE. Our data provide molecular insight into the mechanism of IFN-a signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment. Cellular & Molecular Immunology

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Section: Discussionsupporting

confidence: 43%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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“…OSM activates Stat3 robustly in NIH3T3 cells (10) and was chosen as a ligand to activate Stat3 at maximum level for genome wide screening of Stat3 target genes. Because ligandactivated STATs become de-phosphorylated and inactivated rapidly (32,33), a 30-min OSM treatment time point was chosen to capture as many direct Stat3 target genes as possible, as well as to make it feasible for a scaled up ChIP assay. NIH3T3 cells were treated with OSM for 30 min, and ChIP assays were performed with a Stat3-specific antibody.…”

Section: Identification Of Direct Stat3 Target Genes By Genome-widementioning

confidence: 99%

Identification of Novel Direct Stat3 Target Genes for Control of Growth and Differentiation

Snyder

Huang

Zhang

2008

Journal of Biological Chemistry

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Signal transducer and activator of transcription 3 (Stat3) is a key regulator of gene expression in response to signaling of the glycoprotein 130 (gp130) family cytokines, including interleukin 6, oncostatin M, and leukemia inhibitory factor. Many efforts have been made to identify Stat3 target genes and to understand the mechanism of how Stat3 regulates gene expression. Using the microarray technique, hundreds of genes have been documented to be potential Stat3 target genes in different cell types. However, only a small fraction of these genes have been proven to be true direct Stat3 target genes. Here we report the identification of novel direct Stat3 target genes using a genome-wide screening procedure based on the chromatin immunoprecipitation method. These novel Stat3 target genes are involved in a diverse array of biological processes such as oncogenesis, cell growth, and differentiation. We show that Stat3 can act as both a repressor and activator on its direct target genes. We further show that most of the novel Stat3 direct target genes are dependent on Stat3 for their transcriptional regulation. In addition, using a physiological cell system, we demonstrate that Stat3 is required for the transcriptional regulation of two of the newly identified direct Stat3 target genes important for muscle differentiation.The signal transducer and activator of transcription (STAT) 2 family of transcriptional regulators is activated in response to extracellular signaling proteins, including cytokines and growth factors (1, 2). When cytokines bind to their cell surface receptors, the receptor-associated JAK tyrosine kinases become activated and in turn phosphorylate a single tyrosine residue in the STAT molecule. The phosphorylated STATs then enter the nucleus as dimers and bind to specific DNA sequences in the promoters of their target genes to regulate transcription. Although the seven members of the STAT family have similarity in their molecular structure and function, they play diverse physiological roles in a wide variety of biological processes (3).One member of the STAT family, Stat3, mediates the signaling of cytokines that share the gp130 receptor chain, which include interleukin-6, oncostatin M (OSM), and leukemia inhibitory factor (LIF) (4, 5). In response to gp130 ligand stimulation, Stat3 is phosphorylated on Tyr-705 and forms dimers through phosphotyrosine-Src homology 2 domain interactions (6). The dimerized Stat3 molecules enter the nucleus and bind to a consensus DNA sequence in the promoters of its target genes to regulate transcription (7). The transcriptional activity of Stat3 is mediated by its transcription activation domain located in the carboxyl-terminal end of the molecule (8). In addition to the tyrosine phosphorylation, the Stat3 transcription activation domain contains a serine residue (Ser-724) that is also phosphorylated to achieve maximum transcription activity (9, 10). Analyses of Stat3-dependent enhancersomes demonstrate that Stat3 interacts and recruits other transcription factors and ...

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“…In this case, the role of the protein kinase activating STAT1 on serine becomes critical. Previously different kinases were implicated in S727 STAT1 phosphorylation, including p38 kinase in response to lipopolysaccharide or ultraviolet (UV); p38 kinase, ERKs, c-Jun NH 2 -terminal kinases (JNKs), PI3K, 3-phosphoinositide-dependent protein kinase I (PDK1) and p90 ribosomal S6 kinase (p90RSK2) in the cellular response to UVB; p38 kinase, JNK, PKCd, CaMKII in response to INFg (Kovarik et al, 1999;Nair et al, 2002;Xu et al, 2005;Zykova et al, 2005); and PKC in B-CCL patients (Frank et al, 1997). In this report, for the first time, we provide evidence that CK2 is involved in STAT1 phosphorylation.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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B Cell Antigen Receptor Signaling Enhances IFN-γ-Induced Stat1 Target Gene Expression Through Calcium Mobilization and Activation of Multiple Serine Kinase Pathways

Cited by 18 publications

References 49 publications

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

Identification of Novel Direct Stat3 Target Genes for Control of Growth and Differentiation

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

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