Similar Datasets
Project description:Microarray of TBK1 WT and Mutant pancreatic tumors in the KIC model
| PRJNA534328 | ENA
Project description:TBK1 Regulates Regeneration of Pancreatic b-cells
| PRJNA563022 | ENA
Project description:b-cell proliferation induction is one of the most tangible therapeutic strategies to restore b-cell mass. However, this approach has proven challenging due to a remarkable resistance of adult human b-cells to proliferation. Here we aim to unravel the role of a non-canonical IkB kinase TBK1 (TANK-binding kinase 1), which is predominantly expressed in b-cells in mammalian islets, in regulating cell cycle progression. Genetic silencing of TBK1 in INS-1 832/13 rat b-cell line promoted proliferation of b-cells. Proteomic and transcriptome analyses further revealed changes of proteins and genes critical for cell growth and proliferation, including upregulation of ribosomal proteins and cell cycle regulators, upon depletion of TBK1. TBK1 overexpression decreased sensitivity of b-cells to the elevation of cAMP levels and reduced proliferation of b-cells in a manner dependent on the activity of phosphodiesterase 3 (PDE3). Importantly, pharmacological inhibition of TBK1 using (E)3-(3-phenylbenzo[c]isoxazol-5-yl) acrylic acid (PIAA) augmented proliferation and function of rat and human embryonic stem cell (hESC)-derived insulin-producing b-cells under basal conditions. Diabetogenic insults further induced TBK1 expression and accordingly, PIAA protected b-cells against cytokine- and streptozotocin-induced diabetogenic challenges and promoted b-cell replication. Furthermore, PIAA increased proliferation of β-cells in normal and type 2 diabetic human islets with elevation in insulin secretion. Altogether, these data unveil novel and essential function of TBK1 as a key cell-autonomous negative regulator of b-cell replication and presenting PIAA as a valid therapeutic strategy for augmenting proliferation and function of b-cells.
2020-02-29 | GSE136670 | GEO
Project description:The receptor tyrosine kinase AXL promotes tumor progression, metastasis and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we report that activation of AXL results in TANK-binding kinase 1 (TBK1) phosphorylation, subsequent TBK1-dependent phosphorylation of AKT3 (pAKT3) and nuclear accumulation of pAKT3 and the EMT transcription factor (EMT-TF) Snail. Mechanistically, we show that (i) TBK1 directly binds and phosphorylates AKT3, in an mTORC1 dependent manner. Once activated, AKT3 interacts with Snail and promotes the accumulation of nuclear Snail to drive EMT. Congruently, in human pancreatic ductaladenocarcinoma tissue, nuclear AKT3 co-localizes with Snail and correlates with worse clinical outcome. AKT3 knockout in tumor cells significantly reduced metastatic spread in mice suggesting that selective AKT3 inhibition represents a novel therapeutic avenue for targeting EMT in aggressive cancers.
2024-12-17 | GSE274874 | GEO
Project description:B-DNA-induced gene expression profile in wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats; to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses. Experiment Overall Design: Total RNA was extracted from embryonic fibroblats transfected for 4 h with or without poly(dA-dT)-poly(dT-dA), after which cRNA was synthesized. Preparation of cRNA, hybridization and scanning of the microarray were done according to the manufacturer's instructions (Affymetrix). A microarray (MG U74A version 2; Affymetrix) was used with Microarray Suite software (version 5.0; Affymetrix) and GeneSpring software (Silicon Genetics).
2007-12-07 | E-GEOD-4171 | biostudies-arrayexpress
Project description:Clear cell renal cell carcinoma (ccRCC) is a metabolic disease that is believed to arise from renal proximal convoluted tubule (PCT) epithelial cells. However, the signaling events leading to ccRCC development are not completely understood. Here, we report that a carnitine synthesis enzyme predominantly expressed in PCT cells, γ-butyrobetaine hydroxylase 1 (BBOX1), is a novel ccRCC tumor suppressor. BBOX1 expression is lost in transformed primary renal epithelial cells and ccRCC patient tumors. Restoring BBOX1 expression in ccRCC tumor cells suppresses cell viability in physiological conditions as well as tumor growth and metastasis in xenograft models. Conversely, BBOX1 inhibition increases ccRCC tumor growth. To dissect the mechanism, we performed mass spectrometry analysis of BBOX1 interacting proteins and identified TANK-binding kinase 1 (TBK1). Binding was abrogated by introducing a mutation in BBOX1 that rendered the enzyme inactive. Mechanistically, BBOX1 loss leads to TBK1-dependent mTORC1 activation and increased glycolysis. Thus, the BBOX1-TBK1 axis represents a novel mechanism of dysregulated metabolic signaling offering potential new therapeutic strategies to target ccRCC.
2024-12-23 | GSE261401 | GEO
Project description:mRNA m6A modification is involved in regulation of immune system. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification is unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex and enhanced proteins translation, including IRF3, and facilitated antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which is required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3flfl-lyz2-Cre mice were significantly more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1-/- mice cannot control viral infection and showed higher mortality than control mice due to decreased IRF3 expression. Together, we demonstrated that innate signals activated METTL3 via TBK1, and METTL3 and m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.
2020-10-14 | GSE159421 | GEO
Project description:The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1; The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Experiment Overall Design: Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT)
2009-11-15 | E-GEOD-17643 | biostudies-arrayexpress
Project description:mRNA m6A modification is involved in regulation of immune system. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification is unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex and enhanced proteins translation, including IRF3, and facilitated antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which is required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3flfl-lyz2-Cre mice were significantly more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1—/— mice cannot control viral infection and showed higher mortality than control mice due to decreased IRF3 expression. Together, we demonstrated that innate signals activated METTL3 via TBK1, and METTL3 and m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.
2020-10-19 | GSE159567 | GEO
Project description:mRNA m6A modification is involved in regulation of immune system. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification is unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex and enhanced proteins translation, including IRF3, and facilitated antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which is required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3flfl-lyz2-Cre mice were significantly more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1—/— mice cannot control viral infection and showed higher mortality than control mice due to decreased IRF3 expression. Together, we demonstrated that innate signals activated METTL3 via TBK1, and METTL3 and m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.
2020-10-31 | GSE160481 | GEO