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Gene expression data from MGHU3 bladder cancer cells (FGFR3-Y375C) treated with TAK1 siRNA and/or PD173074

ABSTRACT: The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and direct target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes which regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52452 | GEO | 2013/11/19

SECONDARY ACCESSION(S): PRJNA228972

REPOSITORIES: GEO

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Gene expression data from MGHU3 bladder cancer cells (FGFR3-Y375C) treated with TAK1 siRNA and/or PD173074

Project description:The NFM-NM-:B transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFM-NM-:B activation. A critical mediator of NFM-NM-:B activity is TGFM-NM-2-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and direct target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes which regulate NFM-NM-:B signaling, and promote both NFM-NM-:B transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFM-NM-:B activation. A total of 12 samples of MGHU3 (Y375C) mutant FGFR3 bladder cancer cells (a kind gift from Dr. Margaret Knowles (University of Leeds, Leeds, UK)) were used for array-based gene expression analysis. 3 replicates of each condition: Control siRNA, Control siRNA + PD173074, TAK1 siRNA, and TAK1 siRNA + PD173074.

2013-11-19 | E-GEOD-52452 | biostudies-arrayexpress

Microarray of Human astrocytes transduced with lentivirus expressing FGFR3-TACC3 treated with vehicle, FGFR3-TACC3 treated with the FGFR inhibitor PD173074 for 12h, FGFR3-TACC3-K508M treated with vehicle or empty vector treated with vehicle

Project description:In order to interrogate the transcriptional changes elicited by FGFR3-TACC3, we expressed the FGFR3-TACC3 fusion protein in human astrocytes and compared the global gene expression profiles of cells treated with a specific inhibitor of FGFR3-TK (PD173074) or vehicle. FGFR3-TACC3 expressing HA were also compared with HA that expressed the kinase-inactive FGFR3-TACC3 (FGFR3-TACC3-K508M) and HA transduced with the empty vector. Gene Ontology-guided enrichment map demonstrated that, besides the expected enrichment for mitotic activity, oxidative phosphorylation and mitochondrial biogenesis were the most significant biological functions enriched in HA expressing active FGFR3-TACC3.

2017-10-17 | E-MTAB-6037 | biostudies-arrayexpress

Gene expression data from UMUC-14 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of UMUC-14 cell lines, which endogenously expressed a mutated activated form of FGFR3 (FGFR3-S249C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

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Gene expression data from MGH-U3 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of MGH-U3 cell lines, which were derived from a human bladder tumor and endogenously expressed a mutated activated form of FGFR3 (FGFR3-Y375C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

2018-02-16 | GSE84731 | GEO

Gene expression data from RT112 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of RT112 cell lines, which were derived from a human bladder tumor and endogenously expressed the FGFR3-TACC3 fusion protein, the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

2018-02-16 | GSE84732 | GEO

IRAK4 kinase activity mediates IRF5 activation via IKKβ and TAK1

Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.

2017-10-12 | GSE86234 | GEO

FGFR3-shRNA induced transcriptional changes in RT112 bladder cancer cells

Project description:Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. In this study with a bladder carcinoma cell line expressing inducible FGFR3 shRNAs, we sought to identiy transcriptional targets of FGFR3 and investigate their contribution to bladder cancer development. Bladder cancer cell line RT112 was transduced with a doxycycline-inducible control EGFP shRNA or three independent FGFR3 shRNAs, designated FGFR3 shRNA 2-4, FGFR3 shRNA 4-1 and FGFR3 shRNA 6-16. These four cell lines were treated with or without doxycycline for 48 hr to deplete FGFR3 protein prior to the isolation of mRNA for microarray analysis. Genes that were differentially expressed after doxycycline induction in all three FGFR3-depleted cell lines but not in the control cell line were considered potential FGFR3-regulated genes. Each treatment group was run in triplcates, and there are 24 samples.

2012-11-07 | E-GEOD-41035 | biostudies-arrayexpress

Expression profiling in palatal mesenchymal cells stimulated with TGF-beta2 in the presence and absence of TGFbRI and Tak1 kinase inhibitors

Project description:TGF-beta signaling in neural crest cells is required for normal craniofacial development. This signaling can be transduced via TGF-beta type I receptors (TGFbRI) using Smad-dependent or Smad independent signaling pathways. We used microarrays to identify TGF-beta-responsive genes that are dependent either on TGFbRI kinase, Tak1 kinase or both. Primary palatal mesenchymal cell cultures were established. Cultured cells were stimulated with TGF-beta2 in the presence or absence of TGFbRI kinase and Tak1 kinase inhibitors. Unstimulated cells were used as controls. Total RNAs were isolated and hybridized on Affymetrix microarrays.

2013-03-27 | E-GEOD-45491 | biostudies-arrayexpress

A mass spectrometry analysis of the TAK1 protein complex in Jurkat T cells.

Project description:Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human-PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the higher binding affinity of TAK1 and p38IP for sequential polyUb binding by TAB2 and TAK1, respectively. Moreover, p38IP specifically scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.

2020-04-30 | PXD018330 | Pride

Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation

Project description:Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signalling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating haematopoietic cells, was studied in non-induced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed an enrichment of mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor Î² activated kinase-1 (TAK1), a central player in TLR4 signalling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis and stability, but enhances TAK1 mRNA translation, resulting in elevated TNF-alpha, IL-1beta and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in non-induced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesised TAK1 initiates the inflammatory response of macrophages. In this dataset, we include expression data of RAW 264.7 cells comparing untreated cells and 6h Lipopolysaccharide treatment, and analyse RNAs co-precipitating with hnRNP K dependent on LPS treatment. 12 total samples were analyzed, 6 samples of 2 biological replicates.

2014-07-01 | E-GEOD-48463 | biostudies-arrayexpress

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