Constitutive Activation of NF-kB Inducing Kinase (NIK) in the Mesenchymal Lineage Drives Spontaneous Soft Tissue Sarcoma
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ABSTRACT:
PROVIDER: PRJNA665383 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12703142_1.fastq.gz | Fastqsanger.gz | |||
| SRR12703142_2.fastq.gz | Fastqsanger.gz | |||
| SRR12703143_1.fastq.gz | Fastqsanger.gz | |||
| SRR12703143_2.fastq.gz | Fastqsanger.gz | |||
| SRR12703144_1.fastq.gz | Fastqsanger.gz |
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Project description:Aberrant NF-kB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-kB signaling can be modeled in transgenic mice upon activation of a conditional NF-kB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast Specific Protein (Fsp1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB (Relb) immunostaining, confirming activation of alternative NF-kB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for SMA (Acta2), although vimentin (Vim) staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 (Ptprc) and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for CK19 (Krt19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-kB related biological processes. We conclude that constitutive activation of the alternative NF-kB pathway in the mesenchymal linage drives spontaneous sarcoma and provides a novel mouse model for NF-kB related sarcomas.
2020-09-25 | GSE158479 | GEO
Project description:2 This project is to identify the potential neddylation sites in human NF-kB inducing kinase (A.k.a. Map3K14). NIK-HA or NIK-HA in combination with FLAG-NEDD8 were co-expressed in HEK293T cells. NIK-HA were pulled down via denaturing immunoprecipitation protocol, subject to SDS-PAGE, in-gel trypsin digestion, and Nano LC-MS/MS Analysis. The potential peptides containing K-GG sites were identified.
2023-03-10 | PXD038653 | Pride
Project description:Studies from global loss-of-function mutants suggest that alternative NF-kB downstream of NF-kB inducing kinase (NIK) is a cell-intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx-Cre;NT3 animals (NT3-Cre+), which bear a constitutively active NIK allele (NT3) driven by Osx-Cre, were compared to their Cre-negative, Control (Ctrl) littermates. NT3-Cre+ mice had elevated serum P1NP and CTX levels. Despite this high turnover state, microCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3-Cre+ mice exhibited a greater anabolic response following mechanical loading compared to controls. We next performed RNA-Seq on non-loaded and loaded tibiae to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3-Cre+ mice. Hierarchical clustering revealed two main transcriptional programs: one loading-responsive and the other NT3 transgene-driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase and growth factor activities including Wnts, as well as a calcium-response signature in NT3-Cre+ limbs. The promoters of these GO-term associated genes, including many known to be bone-anabolic, were highly enriched for multiple kB recognition elements (kB-RE) relative to the background frequency in the genome. The loading response in NT3-Cre+ mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10-fold more differentially expressed genes (DEGs) in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple kB-RE in their promoters. Therefore, both transcriptional programs (loading-responsive and NT3 transgene-driven) are modulated by NF-kB. Our studies uncover a previously unrecognized role for NF-kB in the promotion of both basal and mechanically-stimulated bone formation.
2019-06-25 | GSE133212 | GEO
Project description:To generate an efficient defense against begomovirus, we modulated the activity of the immune defense receptor NIK (NSP-Interacting Kinase) in tomato plants; NIK is a virulence target of the begomovirus NSP during infection. Replacing threonine-474 with aspartate (T474D) within the kinase activation loop promoted the constitutive activation of NIK-mediated defenses. This activation resulted in the down-regulation of translation-related genes and the suppression of global translation in T474D-overexpressing tomato lines. We also found that T474D-induced defense-related transcripts were associated with polysomes and immune proteins, which accumulated to detectable levels in T474D leaves. Consistent with these findings, T474D transgenic lines were tolerant to the tomato-infecting begomoviruses ToYSV and ToSRV. We propose that NIK mediates an anti-viral response via translation suppression and immune system induction. Global variation on gene expression induced by NIK expression and virus infection using total RNA from mock-inoculated and ToYSV-infected tomato wild-type plants, mock-inoculated and infected 35S::NIK1-4 overexpressing lines and mock-inoculated and infected 35S::T474D overexpressing lines. File map_itag23.csv correlates the ITAG 2.3 cDNA ID with the 21 bp reads in file Profiles_with_differential_expressions.csv.
2013-12-17 | E-GEOD-38028 | biostudies-arrayexpress
Project description:To generate an efficient defense against begomovirus, we modulated the activity of the immune defense receptor NIK (NSP-Interacting Kinase) in tomato plants; NIK is a virulence target of the begomovirus NSP during infection. Replacing threonine-474 with aspartate (T474D) within the kinase activation loop promoted the constitutive activation of NIK-mediated defenses. This activation resulted in the down-regulation of translation-related genes and the suppression of global translation in T474D-overexpressing tomato lines. We also found that T474D-induced defense-related transcripts were associated with polysomes and immune proteins, which accumulated to detectable levels in T474D leaves. Consistent with these findings, T474D transgenic lines were tolerant to the tomato-infecting begomoviruses ToYSV and ToSRV. We propose that NIK mediates an anti-viral response via translation suppression and immune system induction.
2013-12-17 | GSE38028 | GEO
Project description:The genetic programs that maintain hematopoiesis during steady state in physiologic conditions are different from those activated during stress. Here we show that hematopoietic stem cells (HSCs) with deficiencies in components of the alternative NFkB pathway (the NFkB inducing kinase, NIK, and the downstream molecule NFkB2) had a defect in response to stressors such as supraphysiological doses of cytokines, chemotherapy and hematopoietic transplantation. NIK-deficient mice had peripheral blood and bone marrow leukocyte numbers within normal ranges (except for the already reported defects in B-cell maturation), however, HSCs showed significantly slower expansion capacity in in vitro cultures compared to wild type HSCs. This was due to a delayed cell cycle and increased apoptosis. In vivo experiments showed that NIK-deficient HSCs did not recover at the same pace as controls when challenged with myeloablative chemotherapy. Finally, NIK-deficient HSCs showed a significantly decreased competitive repopulation capacity in vivo. Using HSCs from mice deficient in one of two downstream targets of NIK, i.e., either NFkB2 or c-Rel, only NFkB2 deficiency recapitulated the defects detected with NIK-deficient HSCs. Our results underscore the role of NIK and the alternative NFkB pathway for the recovery of normal levels of hematopoiesis after stress.
2014-11-29 | GSE63702 | GEO
Project description:Arabidopsis was transformed with the NIK receptor or the mutant T474D NIK receptor and infected with CaLCuV. The global variation of gene expression was analysed by RNA-seq at 10 days post inoculation and 20 days post inoculation and differential gene expression was determinated in comparison with mock inoculated Arabidopsis lines. Pairwise comparison between mock inoculated and infected genotypes (WT,NIK-expressing lines and T474D-expressing lines) at 10 dpi and 20 dpi
2014-04-21 | E-GEOD-56922 | 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. 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:Our findings establish NIK as a pivotal regulator of T cell metabolism in anti-tumor immunity and highlight a posttranslational mechanism of metabolic regulation involving the G6PD-NADPH redox system. CoIP assays revealed a strong physical interaction between NIK and G6PD in both T cells and transiently transfected 293 cells, suggesting G6PD to be a direct target of NIK. Using a phosphoprotein gel analysis approach, we demonstrated that NIK expression stimulated G6PD phosphorylation. To further study the mechanism, we performed mass spectrometry identify phosphorylation sites of G6PD stimulated by NIK
2020-10-05 | PXD020943 | Pride
Project description:Arabidopsis was transformed with the NIK receptor or the mutant T474D NIK receptor and infected with CaLCuV. The global variation of gene expression was analysed by RNA-seq at 10 days post inoculation and 20 days post inoculation and differential gene expression was determinated in comparison with mock inoculated Arabidopsis lines.
2014-04-21 | GSE56922 | GEO