Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA283207 | ENA |
REPOSITORIES: ENA
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Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.
2017-06-12 | GSE68615 | GEO
Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.
2020-08-22 | GSE119961 | GEO
Project description:As such, TNF triggers the canonical NF-?B pathway to induce a nuclear NF-?B activity composed of the RelA:p50 dimer in WT cells. Nfkb2 encodes p100, which regulates the activity of the RelB NF-?B heterodimers during immune cell-differentiation via the noncanonical pathway. Our biochemical analyses revealed that an absence of p100 instead repositions RelB under the control of the TNF-activated canonical pathway. Indeed, chronic TNF treatment of Nfkb2-/- cells activates the RelA:p50 dimer and an additional RelB:p50 dimer. On the other hand, TNF stimulation of Relb-/-Nfkb2-/- and Rela-/-Nfkb2-/- MEFs exclusively activated the RelA:p50 dimer and the RelB:p50 dimer, respectively. We treated this panel of knockout MEFs with TNF for 6h before being subjected to microarray mRNA analysis. We also included in our analysis WT MEFs and Rela-/-Relb-/-Rel-/- MEFs, which served as a negative control. Our analyses revealed overlapping and distinct gene-expression specificities of RelA:p50 and RelB:p50 dimers activated in mutant cells in response to TNF.
2019-06-13 | GSE99980 | GEO
Project description:The transcription factor, NF-кB, plays a central role in the response to DNA damage. This ubiquitous family of proteins is made up of five subunits: p50 (NF-κB1, p105), p52 (NF-κB2, p100), p65 (relA), relB, and crel that appear in their mature form as dimers. Following stimulation, NF-κB dimers translocate to the nucleus where they bind specific consensus elements (κB-sites) in the promoter region of genes involved in cell survival, inflammation and the immune system. While there is a general propensity of NF-кB to mediate survival, this is not always the case and several reports note the pro-apoptotic nature of the NF-кB pathway. In examining the NF-кB response to DNA damage, we have found that the p50 subunit plays a central role in modulating cytotoxicity following TMZ treatment in malignant glioma. In the current study, given the importance of p50 to the cytotoxic response to TMZ, we set out to identify NF-кB-dependent factors that modulate the response to TMZ. U-87 glioma cells stably transfected with either control-shRNA or p105-shRNA and subsequently treated with temozolomide (TMZ) were selected for RNA extraction and hybridization on Affymetrix microarrays. Each category contains 3 biologic replicates.
2015-01-29 | E-GEOD-65363 | biostudies-arrayexpress
Project description:The transcription factor, NF-кB, plays a central role in the response to DNA damage. This ubiquitous family of proteins is made up of five subunits: p50 (NF-κB1, p105), p52 (NF-κB2, p100), p65 (relA), relB, and crel that appear in their mature form as dimers. Following stimulation, NF-κB dimers translocate to the nucleus where they bind specific consensus elements (κB-sites) in the promoter region of genes involved in cell survival, inflammation and the immune system. While there is a general propensity of NF-кB to mediate survival, this is not always the case and several reports note the pro-apoptotic nature of the NF-кB pathway. In examining the NF-кB response to DNA damage, we have found that the p50 subunit plays a central role in modulating cytotoxicity following TMZ treatment in malignant glioma. In the current study, given the importance of p50 to the cytotoxic response to TMZ, we set out to identify NF-кB-dependent factors that modulate the response to TMZ.
2015-01-29 | GSE65363 | GEO
Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course for each cell type (wt, relA-/-, relB-/-) two time points were analysed (0h as control and 10h) using 3 technical replicates resulting in 18 samples in total
2008-12-17 | E-GEOD-11963 | biostudies-arrayexpress
Project description:CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, that could account for the immune landscape remodeling in TNBC cells
2021-12-06 | PXD027196 | Pride
Project description:The malignant cells of Hodgkin's lymphoma are characterized by a constitutive activation of the canonical as well as the non-canonical NF-κB signaling cascades. We carried out genome-wide localization and expression profiling experiments in the Hodgkin lymphoma cell line L1236 for the canonical and non-canonical NF-κB pathway components p65, p50 and p52, RelB, respectively. We found that the single NF-κB subunits bind to overlapping, but distinct cistromes by using consensus motifs of high similarity.
2016-02-18 | GSE63736 | GEO
Project description:RNA-seq was used to characterize the NF-κB transcription factor -mediated regulation of B-cell genome wide target genes upon inducible LMP1 expression . We created an inducible stable EBV-negative Akata Burkitt Lymphoma cell line expressing LMP1 wildtype followed by stable CRISPR knockout of the individual NF-κB transciption factors (p52, RelB, p50, cRel or RelA) and 24 hours 250ng/ml doxycycline-induced LMP1 expression.
2024-01-30 | GSE247495 | GEO
Project description:To elucidate the mechanisms responsible for cytoprotective effects of tumor necrosis factor receptor activated factor 2 (TRAF2) in the heart, we employed genetic gain and loss of function studies ex vivo and in vivo in mice with cardiac restricted overexpression of TRAF2 (Myh6-TRAF2LC). Crossing Myh6-TRAF2LC mice with mice lacking canonical signaling (Myh6-TRAF2LC/Myh6-IκBαΔN) abrogated the cytoprotective effects of TRAF2 ex vivo. In contrast, inhibiting the JAK/STAT pathway did not abrogate the cytoprotective effects of TRAF2. Transcriptional profiling of wild-type, Myh6-TRAF2LC, Myh6-TRAF2LC/Myh6-IκBαΔN hearts suggested that the non-canonical NF-κB signaling pathway was upregulated in the Myh6-TRAF2LC hearts. Western blotting and ELISA for the NF-κB family proteins p50, p65, p52 and RelB on nuclear and cytoplasmic extracts from naïve 12 week old wild-type, Myh6-TRAF2LC and Myh6-TRAF2LC/Myh6-IκBαΔN mouse hearts showed increased expression levels and increased DNA binding of p52 and RelB, which are NF-κB family members, whereas there was no increase in expression nor DNA binding of the p50 and p65 subunits. Crossing Myh6-TRAF2LCmice with RelB-/+mice (Myh6-TRAF2LC/RelB-/+) attenuated the cytoprotective effects of TRAF2 ex vivo and in vivo. Viewed together, these results suggest that cross-talk between the canonical and non-canonical NF-κB signaling pathways is required for mediating the cytoprotective effects of TRAF2.
2017-12-15 | GSE107668 | GEO