STAT3 phosphorylation at serine 727 activates specific genetic programs and promotes clear cell renal cell carcinoma (ccRCC) aggressiveness
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE245862 | GEO | 2023/11/15
REPOSITORIES: GEO
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Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long-lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL-PCs, but negatively regulates MBC output.
2023-07-06 | GSE212542 | GEO
Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long- lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL- PCs, but negatively regulates MBC output.
2023-07-06 | GSE212541 | GEO
Project description:Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and EGFR, respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
2022-01-09 | GSE193179 | GEO
Project description:Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and EGFR, respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
2022-01-09 | GSE193178 | GEO
Project description:In the related study, to determine whether DUSP2 definitively served as a phosphatase for STAT3, an in vitro phosphatase assay was used. Using S-tag beads, p-STAT3 was pulled down from IL-6 stimulated HEK293T cells transfected with STAT3-S-Tag. DUSP2 or control protein, which was purified from HEK293T cells transfected with DUSP2-FLAG or empty vector through extraction with anti-FLAG beads and elution with FLAG peptides, were incubated with p-STAT3-S-Tag-beads in phosphatase buffer. Then bound proteins were eluted and subjected to MS analysis. When compared with the control, incubation of STAT3 and DUSP2 led to dephosphorylation of two STAT3 residues that have been reported to promote its activity, namely tyrosine 705 and serine 727.
2015-10-13 | PXD002743 | Pride
Project description:Gene regulation by cytokine-activated STAT transcription factors requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation was reported to occur upon promoter binding by an unknown kinase. Here we show that the Mediator CDK8 module phosphorylates S727 of the STAT1 TAD in the interferon (IFN) signaling pathway as well as the TADs of other STATs. Microarray analysis reveals that CDK8-mediated STAT1 TAD phosphorylation positively or negatively regulates over 40% of IFN-gamma-responsive genes, and RNA polymerase II occupancy correlates with gene expression changes. This selective regulation occurs despite CDK8 occupancy and STAT1 S727 phosphorylation at both S727 phosphorylation-dependent and -independent IFN-gamma target genes. Independently of its role as STAT1 S727 kinase CDK8 acts as a positive regulator of IFN-gamma responses. These data reveal a dual input of CDK8 in STAT1-controlled transcription and propose a key role for CDK8 in TAD phosphorylation of other STATs during cytokine responses.
2013-02-28 | GSE40728 | GEO
Project description:This study is to identify downstream genes regulated by STAT3 in response cytosolic acidification. Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment, cancer cells maintain alkaline intracellular pH (≥7.4) that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration and invasion. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a key player in the maintenance of alkaline cytosolic pH. STAT3 associates with the vacuolar H+-ATPase on lysosomal membranes in a coiled coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing and increasing cytosolic and lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild type STAT3 as well as STAT3 mutants unable to activate target genes (Tyr-705-Phe and DNA binding mutant) or to regulate mitochondrial respiration (Ser-727-Ala). Upon cytosolic acidification, phospho-Tyr-705-STAT3 is rapidly dephosphorylated, transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium and to enhance cell survival. These data reveal STAT3 as a regulator of intracellular pH, and vice versa intracellular pH as a regulator of STAT3 localization and activity.
2018-01-03 | GSE108495 | GEO
Project description:Epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET) processes are proposed to be a driving force of cancer metastasis. By studying metastasis in bone marrow-derived mesenchymal stem cell (BM-MSC)-driven lung cancer models, microarray time-series data analysis by systems biology approaches revealed BM-MSC-induced signaling triggers early dissemination of CD133+/CD83+ cancer stem cells (CSCs) from primary sites shortly after STAT3 activation but promotes proliferation towards secondary sites. The switch from migration to proliferation was regulated by BM-MSC-secreted LIF and activated LIFR/p-ERK/pS727-STAT3 signaling to promote early disseminated cancer cells MET and premetastatic niche formation. Then, tumor-tropic BM-MSCs circulated to primary sites and triggered CD151+/CD38+ cells acquiring EMT-associated CSC properties through IL6R/pY705-STAT3 signaling to promote tumor initiation and were also attracted by and migrated towards the premetastatic niche. In summary, STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates the EMT-MET switch within the distinct molecular subtypes of CSCs to complete the metastatic process.
2020-10-01 | GSE158824 | GEO
Project description:Gene regulation by cytokine-activated STAT transcription factors requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation was reported to occur upon promoter binding by an unknown kinase. Here we show that the Mediator CDK8 module phosphorylates S727 of the STAT1 TAD in the interferon (IFN) signaling pathway as well as the TADs of other STATs. Microarray analysis reveals that CDK8-mediated STAT1 TAD phosphorylation positively or negatively regulates over 40% of IFN-gamma-responsive genes, and RNA polymerase II occupancy correlates with gene expression changes. This selective regulation occurs despite CDK8 occupancy and STAT1 S727 phosphorylation at both S727 phosphorylation-dependent and -independent IFN-gamma target genes. Independently of its role as STAT1 S727 kinase CDK8 acts as a positive regulator of IFN-gamma responses. These data reveal a dual input of CDK8 in STAT1-controlled transcription and propose a key role for CDK8 in TAD phosphorylation of other STATs during cytokine responses. STAT1 WT and STAT1 S727A mouse fibroblasts were treated with siRNA to CDK8 (siCdk8 smart pool, On Target Plus, Dharmacon) and control siRNA (siCtrl) and stimulated with IFN-gamma for 4 h or left untreated. Total RNA from three independent experiments for each treatment and each genotype was isolated from cells using Trizol reagent (Invitrogen) following the manufactures protocol and used for expression analysis using Agilent Whole Mouse Genome Microarrays, 8x60K. Standard protocols for labeling and hybridization were followed. In brief, fluorescent cRNA was generated using Low Input Quick Amp Labeling Kit (Agilent). The amplified cyanine 3-labeled cRNA samples were then purified using SV Total RNA Isolation System (Promega) and hybridized to microarray slides. Microarray slides were washed and scanned with an Agilent Scanner. Note: The outlier array #10 [SA.CDK.gamma.R3] was removed from subsequent analysis and its processed data was not provided. However, its raw data file has been linked as a supplementary file at the foot of the Series record.
2013-02-28 | E-GEOD-40728 | biostudies-arrayexpress
Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
2020-05-26 | PXD010612 | Pride