3' mRNA Sequencing of Mouse Small Cell Lung Cancer tissue
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB53995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10762200.fastq.gz | Fastqsanger.gz | |||
| ERR10762201.fastq.gz | Fastqsanger.gz | |||
| ERR10762202.fastq.gz | Fastqsanger.gz | |||
| ERR10762203.fastq.gz | Fastqsanger.gz | |||
| ERR10762204.fastq.gz | Fastqsanger.gz |
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Project description:In response to DNA double strand breaks (DSBs), the ATM kinase activates NF-κB factors to stimulate gene expression changes that promote survival and allow time for cells to repair damage. In cell lines, ATM can activate NF-κB transcription factors via two independent, convergent mechanisms. One is ATM-mediated phosphorylation of nuclear NF-κB essential modulator (Nemo) protein, which leads to monoubiquitylation and export of Nemo to the cytoplasm where it engages the IκB kinase (IKK) complex to activate NF-κB. Another is DSB-triggered migration of ATM into the cytoplasm where it promotes monoubiquitylation of Nemo and resulting IKK-mediated activation of NF-κB. ATM has many other functions in the DSB response beyond activation of NF-κB, and Nemo activates NF-κB downstream of diverse stimuli, including developmental or proinflammatory stimuli such as lipopolysaccharides (LPS). To elucidate the in vivo role of DSB-induced, ATM-dependent changes in expression of NF-κB-responsive genes, we generated mice expressing phosphomutant Nemo protein lacking consensus SQ sites for phosphorylation by ATM or related kinases. We demonstrate that these mice are viable/healthy, fertile, and exhibit overall normal B and T lymphocyte development. Moreover, treatment of their B lineage cells with LPS induces normal NF-κB-regulated gene expression changes. Furthermore, in marked contrast to results from a pre-B cell line, primary B lineage cells expressing phosphomutant Nemo treated with the genotoxic drug etoposide induce normal ATM- and Nemo-dependent changes in expression of NF-κB-regulated genes. Our data demonstrate that ATM-dependent phosphorylation of Nemo SQ motifs in vivo is dispensable for DSB-signaled changes in expression of NF-κB-regulated genes.
2024-08-08 | GSE264315 | GEO
Project description:Oxidative and genotoxic stresses activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors, but their physiological roles remain incompletely defined. We created the NEMODK mouse model with germline arginine substitutions at NEMO (NF-κB essential modulator) lysines 270 and 302, key sites for post-translational modifications selectively induced by these intracellular stresses to enable NF-κB signaling in vitro. NEMODK mice exhibited B cell-intrinsic defects in the generation of germinal center B cells and humoral responses. Mechanistically, NEMODK B cells displayed a CD40-specific NF-κB signaling defect, unrelated to acute canonical and delayed noncanonical NF-κB activity, which was accompanied by the lack of sustained NEMO monoubiquitination downstream of mitochondrial reactive oxygen species generation without relying on nuclear DNA damage. This specifically reduced persistent RelA activity and a failure to mount transcriptomic and epigenetic changes critical for homotypic B cell aggregation, cell proliferation, class switch recombination and antibody secreting cell generation. Thus, CD40 induces a uniquely sustained NEMO modification and persistent RelA transcriptional activity to efficiently generate class-switched antibodies.
2026-06-09 | GSE325580 | GEO
Project description:Oxidative and genotoxic stresses activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors, but their physiological roles remain incompletely defined. We created the NEMODK mouse model with germline arginine substitutions at NEMO (NF-κB essential modulator) lysines 270 and 302, key sites for post-translational modifications selectively induced by these intracellular stresses to enable NF-κB signaling in vitro. NEMODK mice exhibited B cell-intrinsic defects in the generation of germinal center B cells and humoral responses. Mechanistically, NEMODK B cells displayed a CD40-specific NF-κB signaling defect, unrelated to acute canonical and delayed noncanonical NF-κB activity, which was accompanied by the lack of sustained NEMO monoubiquitination downstream of mitochondrial reactive oxygen species generation without relying on nuclear DNA damage. This specifically reduced persistent RelA activity and a failure to mount transcriptomic and epigenetic changes critical for homotypic B cell aggregation, cell proliferation, class switch recombination and antibody secreting cell generation. Thus, CD40 induces a uniquely sustained NEMO modification and persistent RelA transcriptional activity to efficiently generate class-switched antibodies.
2026-06-09 | GSE325579 | GEO
Project description:Oxidative and genotoxic stresses activate NF-κB signaling through intracellular pathways distinct from those initiated by membrane receptors, but their physiological roles remain incompletely defined. We created the NEMODK mouse model with germline arginine substitutions at NEMO (NF-κB essential modulator) lysines 270 and 302, key sites for post-translational modifications selectively induced by these intracellular stresses to enable NF-κB signaling in vitro. NEMODK mice exhibited B cell-intrinsic defects in the generation of germinal center B cells and humoral responses. Mechanistically, NEMODK B cells displayed a CD40-specific NF-κB signaling defect, unrelated to acute canonical and delayed noncanonical NF-κB activity, which was accompanied by the lack of sustained NEMO monoubiquitination downstream of mitochondrial reactive oxygen species generation without relying on nuclear DNA damage. This specifically reduced persistent RelA activity and a failure to mount transcriptomic and epigenetic changes critical for homotypic B cell aggregation, cell proliferation, class switch recombination and antibody secreting cell generation. Thus, CD40 induces a uniquely sustained NEMO modification and persistent RelA transcriptional activity to efficiently generate class-switched antibodies.
2026-06-09 | GSE325910 | GEO
Project description:Lentiviral accessory genes enhance replication through diverse mechanisms. HIV-1 accessory protein Vpr modulates the host DNA damage response (DDR) at multiple steps through DNA damage, cell cycle arrest, the degradation of host proteins, and both the activation and repression of DDR signaling. Vpr also alters host and viral transcription; however, the connection between Vpr-mediated DDR modulation and transcriptional activation remains unclear. Here, we determined the cellular consequences of Vpr-induced DNA damage using Vpr mutants that allow us to separate the ability of Vpr to induce DNA damage from cell cycle arrest and other DDR phenotypes including host protein degradation and repression of DDR. RNA-sequencing of cells expressing Vpr or Vpr mutants identified that Vpr alters cellular transcription through mechanisms both dependent and independent of cell cycle arrest. In tissue-cultured U2OS cells and primary human monocyte-derived macrophages (MDMs), Vpr-induced DNA damage activates the ATM-NEMO pathway and alters cellular transcription via NF-κB/RelA signaling. HIV-1 infection of primary MDMs validated Vpr-dependent NF-κB transcriptional activation during infection. Both virion delivered and de novo expressed Vpr induced DNA damage and activated ATM-NEMO dependent NF-κB transcription, suggesting that engagement of the DDR and transcriptional reprogramming can occur during early and late stages of viral replication. Together, our data identifies a mechanism by which Vpr activates NF-κB through DNA damage and the ATM-NEMO pathway, which occur independent of cell cycle arrest. We propose this is essential to overcoming restrictive environments, such as in macrophages, to enhance viral transcription and replication.
2024-08-23 | GSE253779 | GEO
Project description:Many immune responses depend upon activation of NF-κB, a key transcription factor in the elicitation of a cytokine response. Here we show that N4BP1 inhibits TLR-dependent activation of NF-κB by interacting with the NF-κB signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like (ubiquitin conjugation to ER degradation) domains in N4BP1 mediate the interaction with the NEMO COZI domain. Both in vitro and in mice, N4bp1 deficiency specifically enhances TRIF-independent (TLR2, TLR7, or TLR9-mediated), but not TRIF-dependent (TLR3 or TLR4-mediated), NF-κB activation leading to increased production of proinflammatory cytokines. In response to TLR4 or TLR3 activation, TRIF causes activation of caspase-8, which cleaves N4BP1 distal to residues D424 and D490 and abolishes its inhibitory effect. N4bp1-/- mice also exhibit diminished numbers of T cells in the peripheral blood. Our work identifies N4BP1 as an inhibitory checkpoint protein that must be overcome to activate NF-κB, and a TRIF-initiated caspase-8-dependent mechanism by which this is accomplished.
2021-02-08 | GSE165916 | GEO
Project description:Signal transduction by the NF-kappaB pathway is a key regulator of a host of cellular responses to extracellular and intracellular messages. The NEMO adaptor protein lies at the top of this pathway and serves as a molecular conduit, connecting signals transmitted from upstream sensors to the downstream NF-kappaB transcription factor and subsequent gene activation. The position of NEMO within this pathway makes it an attractive target from which to search for new proteins that link NF-kappaB signaling to additional pathways and upstream effectors. In this work, we have used protein microarrays to identify novel NEMO interactors. A total of 112 protein interactors were identified, with the most statistically significant hit being the canonical NEMO interactor IKKbeta, with IKKalpha also being identified. Of the novel interactors, more than 30% were kinases, while at least 25% were involved in signal transduction. Binding of NEMO to several interactors, including CALB1, CDK2, SAG, SENP2 and SYT1, was confirmed using GST pulldown assays and coimmunoprecipitation, validating the initial screening approach. Overexpression of CALB1, CDK2 and SAG was found to stimulate transcriptional activation by NF-kappaB, while SYT1 overexpression repressed TNFalpha-dependent NF-kappaB transcriptional activation in human embryonic kidney cells. Corresponding with this finding, RNA silencing of CDK2, SAG and SENP2 reduced NF-kappaB transcriptional activation, supporting a positive role for these proteins in the NF-kappaB pathway. The identification of a host of new NEMO interactors opens up new research opportunities to improve understanding of this essential cell signaling pathway. For microarray screening, Invitrogen Protoarray v4.0 protein microarrays were used. Human NEMO expressed as a C-terminal GST fusion was purified from E. coli lysates and labelled with biotin. NEMO or biotinylated GST were applied to the microarrays and binding partners detected using streptavidin-Alexa Fluor 647. Significant interactors on both arrays were detected using Invitrogen Protoarray Prospector software and a Z-score cutoff of 3.0. Following subtraction of interactors present on the GST control array, a final set of significant NEMO interactors was derived. Full experimental details are supplied in Fenner, B. J., Scannell, M. & Prehn, J. H. M. (2010). Expanding the substantial interactome of NEMO using protein microarrays. PLoS ONE (in press).
2010-06-19 | E-GEOD-19841 | biostudies-arrayexpress
Project description:Chronic activation of NF-κB contributes to senescence and aging, but how endogenous DNA damage engages this pathway in vivo remains unclear. NF-κB can be activated by an atypical pathway in which genotoxic stress triggers ATM-dependent sumoylation of the regulatory subunit NEMO, yet the role of this axis in senescence and aging has not been tested. Here we introduced a knock-in NEMO double-lysine mutant (NEMO-DK) that prevents sumoylation at the conserved sites required for DNA damage-induced NF-κB activation, and examined its impact in Ercc1-/∆ mice, a model of accelerated, DNA damage-driven aging. We demonstrated that NEMO-DK markedly reduced senescence and SASP in primary fibroblasts and across multiple tissues, improved liver and skeletal muscle pathology, attenuated intervertebral disc degeneration, significantly delayed the onset and progression of aging symptoms and extended healthspan. These findings identify DNA damage-induced NEMO sumoylation as a key driver of NF-κB-mediated senescence in vivo and suggest that the atypical NF-κB pathway is a potential therapeutic target to mitigate aging-associated diseases.
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Project description:Transcription factor NF-κB regulates cellular responses to environmental cues. For many stimuli NF-κB resides only transiently in the nucleus. Consequently, time-dependent transcriptional outputs are a fundamental feature of NF-κB activation. Here we identify mechanisms that direct kinetic patterns of NF-κB-dependent gene expression and transcriptional outcomes in response to a transient NF-κB-inducing stimulus in B cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-κB activation, we demonstrate that kinetic differences amongst early- and late-activated RELA target genes can be understood based on chromatin configuration prior to cell activation and RELA-dependent priming, respectively. Additionally, we identified genes that were repressed by RELA activation and others that responded to RELA-activated transcription factors. Cumulatively, our studies define an NF-κB-responsive inducible gene cascade in activated B cells.
2018-09-17 | GSE117241 | GEO
Project description:Transcription factor NF-κB regulates cellular responses to environmental cues. For many stimuli NF-κB resides only transiently in the nucleus. Consequently, time-dependent transcriptional outputs are a fundamental feature of NF-κB activation. Here we identify mechanisms that direct kinetic patterns of NF-κB-dependent gene expression and transcriptional outcomes in response to a transient NF-κB-inducing stimulus in B cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-κB activation, we demonstrate that kinetic differences amongst early- and late-activated RELA target genes can be understood based on chromatin configuration prior to cell activation and RELA-dependent priming, respectively. Additionally, we identified genes that were repressed by RELA activation and others that responded to RELA-activated transcription factors. Cumulatively, our studies define an NF-κB-responsive inducible gene cascade in activated B cells.
2018-09-17 | GSE117254 | GEO