Investigating the effect of NIK SMI1, a small molecule inhibitor of NIK, on TWEAK-stimulated Mouse renal proximal tubule-interstitial epithelial cells (RPTEC)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE89195 | GEO | 2017/10/26
SECONDARY ACCESSION(S): PRJNA350616
REPOSITORIES: GEO
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Project description:Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB–inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease. This study compares nine t(11;18)-positive MALT lymphomas (8 from the stomach and 1 from lung) and eight translocation negative MALT lymphomas (all from the stomach) using gene set enrichment analysis (GSEA). All cases were subjected to Affymetrix U133A and U133B microarray analysis. The cases used in this study are the same cases used for the study by Hamoudi et al. (2010) entitled "Differential expression of NF-kB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism" with GEO reference number: GSE18736 and PubMed ID: http://www.ncbi.nlm.nih.gov/pubmed/20520640 All cases were subjected to non-specific filtering to eliminate non-variant probes, then the U133A and U133B probes were collapsed and the collapsed set was subjected to GSEA using the NF-kB target gene set as described in Hamoudi et al. (2010) study mentioned above. The 34 samples in this study are identical to the ones done in the previous series except that the gene set enrichment was done on just those 34 samples and not the complete set.
2011-01-30 | E-GEOD-25527 | biostudies-arrayexpress
Project description:Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB–inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease.
2011-01-30 | GSE25527 | GEO
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).
2015-06-18 | E-GEOD-68317 | biostudies-arrayexpress
Project description:The non-canonical NF-κB signaling cascade is essential for lymphoid organogenesis, B-cell maturation, osteoclast differentiation, and inflammation in mammals, whereas dysfunction of this system is associated with human diseases, including immunological disorders and cancer. While controlled expression of NF-κB Inducing Kinase (NIK) is the rate-limiting step in non-canonical NF-κB activation, mechanisms of inhibition remain largely unknown. Here, we report the identification of the sine oculis homeobox homolog family transcription factors SIX1 and SIX2 as essential inhibitory components of the non-canonical NF-κB signaling pathway. The developmentally silenced SIX-proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit RelA and RelB trans-activation function in a negative feedback circuit. In support of a physiologically pivotal role for SIX-proteins in host immunity, human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/p53-driven lung adenocarcinoma cells from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents, small-molecule activators of the non-canonical NF-κB pathway. Collectively, our study reveals a NIK-SIX signaling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.
2019-03-22 | GSE126535 | GEO
Project description:NF-κB-Inducing Kinase (NIK), which is essential for the activation of the noncanonical NF-κB pathway, regulates diverse processes in immunity, development, and disease. While recent studies have elucidated important functions of NIK in adaptive immune cells and cancer cell metabolism, the role of NIK in metabolic-driven inflammatory responses in innate immune cells remains unclear. Here we demonstrate that NIK-deficient bone marrow-derived macrophages exhibit defects in mitochondrial-dependent metabolism and oxidative phosphorylation (OXPHOS) functions that impair acquisition of a pro-repair, anti-inflammatory phenotype. Subsequently, NIK-deficient mice exhibit skewing of myeloid cells characterized by aberrant eosinophil, monocyte, and macrophage cell populations in the blood, bone marrow, and adipose tissue. Furthermore, NIK-deficient blood monocytes display hyperresponsiveness to bacterial lipopolysaccharide and elevated TNFα production ex vivo, indicative of systemic inflammation. These findings suggest that NIK is required for the metabolic rewiring of mitochondrial respiration that is critical for balancing pro- and anti-inflammatory myeloid immune cell functions. Overall, our work highlights a previously unrecognized role for NIK as a molecular rheostat that fine-tunes immunometabolism in innate immunity and suggests that metabolic dysfunction may be an important driver of inflammatory diseases caused by aberrant NIK expression or activity.
2023-01-20 | GSE223040 | GEO
Project description:Purpose: The goal of this study is to determine the molecular mechanisms involved in the NIK regulation of α cell function. Methods: mRNA profiles of β-Gal control, NIK, and NIK(KA) overexpressed αTC1-6 cells were generated by deep sequencing using an Illumina Hiseq platform. Paired-end clean reads were aligned to the mouse reference genome(Ensemble_GRCm38.89) with TopHat (version 2.0.12), and the aligned reads were used to quantify mRNA expression by using HTSeq-count (version 0.6.1). Conclusion: Our study represents the first detailed analysis of NIK-overexpressing aTC1-6 cell transcriptomes, generated by RNA-seq technology. Our results show that 328 genes were upregulated and 48 genes were downregulated following NIK overexpression. GO analysis indicated that the upregulated genes were primarily related to the immune response. KEGG pathway enrichment analysis showed that immune signaling pathways, including the TNF, NF-κB, and chemokine signaling pathways, were significantly activated by NIK overexpression in aTC1-6 cells, while genes related to metabolism-associated signal pathways were significantly decreased. NIK(KA), the dominant-negative mutant of NIK, does not affect gene expression in aTC1-6 cells.
2018-12-30 | GSE112511 | GEO
Project description:This study aims at identifying genes that are NIK/NF-kappaB2 responsive in murine dendritic cells matured in vivo. Keywords: NIK/NF-kappaB2 responsive genes in dendritic cells after TLR/CD40 signaling
2008-03-05 | GSE7219 | GEO
Project description:Purpose: The goal of this study is to investigate how NIK regulates islet β-cell function. Methods: mRNA profiles of β-Gal-overexpressing, NIK-overexpressing, and NIK(KA)-overexpressing INS-1 832/13 cells were generated by deep sequencing using an Illumina Hiseq platform. Paired-end clean reads were aligned to the rat reference genome (ftp://ftp.ensembl.org/pub/release-90/fasta/rattus_norvegicus/dna/) with TopHat (version 2.0.12), and the aligned reads were used to quantify mRNA expression by using HTSeq-count (version 0.6.1). Conclusion: Our study represents the first detailed analysis of mRNA profiles in NIK-overexpressing and NIK(KA)-overexpressing INS-1 832/13 cells, generated by RNA-seq technology. Our results show that 471 genes were upregulated and 249 genes were downregulated following NIK overexpression. GO analysis indicated that the upregulated genes were primarily related to the immune response. KEGG pathway enrichment analysis showed that immune signaling pathways, including the TNF, NF-κB, antigen processing and presentation signaling pathways, were significantly activated by NIK overexpression in INS-1 832/13 cells, whereas genes related to insulin secretion and regulation of secretion were significantly decreased. NIK(KA), the dominant-negative mutant of NIK, does not induce the expression of genes related to immune response in INS-1 832/13 cells.
2020-07-28 | GSE130121 | GEO
Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity.
2015-06-18 | GSE68317 | GEO
Project description:Introduction: there is growing evidence that the IFN- -related cytokine signature plays a major role supporting the effect of pharmacological blockade of immune checkpoints. The expression of IFN- in cancer cells is repressed by several factors, among them a key role is played by the oncogene EZH2, which in turns is controlled by the non-canonical NF-kB pathway and its upstream kinase, NIK. Methodology: we developed a series of NIK inhibitors and compared the effects on cancer cells of one of them (DMBP5) to an siRNA against NIK via transcriptomic analysis (RNA-seq). Results: mRNA modifications induced by DMBP5 on A375 melanoma cells closely resemble the ones observed with siRNA against NIK. Conclusions: DMBP5 is a very selective and effective non-competitive NIK inhibitor (first in class).
2020-01-08 | GSE106286 | GEO