Ontology highlight
ABSTRACT:
PROVIDER: PRJNA798272 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17652770.fastq.gz | Fastqsanger.gz | |||
| SRR17652771.fastq.gz | Fastqsanger.gz | |||
| SRR17652772.fastq.gz | Fastqsanger.gz | |||
| SRR17652773.fastq.gz | Fastqsanger.gz | |||
| SRR17652774.fastq.gz | Fastqsanger.gz |
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Project description:Emerging evidence indicates that metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. In this study, utilizing a metabolic CRISPR-Cas9 knockout library screen, we observed that loss of Glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably heightens the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B-repressing factor (NKRF), a known inhibitor of NF-κB signaling, to promote NF-κB activity and subsequently facilitate chemoresistance. In response to platinum drug treatment, P38 MAPK phosphorylates GCLM at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM correlates with unfavorable prognosis and poor benefit from standard chemotherapy. Overall, our work shed light on the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.
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Project description:Markus W. Covert, Thomas H. Leung, Jahlionais E. Gaston & David Baltimore. Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 309, 5742 (2005).
Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be "tested". Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field.
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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B. Human subset (GSM303547-GSM303550): Two biological replicates of non-expressing HtTA-LMX1B cells (grown in doxycycline-containing medium) and of LMX1B-expressing HtTA-LMX1B cells (grown for 4 days in doxycycline-free medium) were processed for gene expression array analyses using an Affymetrix platform. Mouse subset (GSM304379-GSM304384): Three kidney samples from newborn wild-type mice and from newborn Lmx1b-/- knock-out mice were processed for gene expression array analyses using an Agilent platform.
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Project description:Detection of bacterial flagellin by the tomato receptors Flagellin sensing 2 (Fls2) and Fls3 triggers activation of pattern-triggered immunity (PTI). We identified a tomato Fls2/Fls3-interacting receptor-like cytoplasmic kinase, Fir1, that is involved in PTI triggered by flagellin perception. Fir1 localized to the plasma membrane and interacted with Fls2 and Fls3 in yeast and in planta. CRISPR/Cas9-generated tomato fir1 mutants were impaired in several immune responses induced by the flagellin-derived peptides flg22 and flgII-28, including resistance to Pseudomonas syringae pv. tomato (Pst) DC3000, production of reactive oxygen species, and enhanced PR1b gene expression, but not MAP kinase phosphorylation. Remarkably, fir1 mutants developed larger Pst DC3000 populations than wild-type plants, whereas no differences were observed in wild-type and fir1 mutants plants infected with the flagellin deficient Pst DC3000deltafliC. fir1 mutants failed to close stomata when infected with Pst DC3000 and Pseudomonas fluorescens, and were more susceptible to Pst DC3000 than wild-type plants when inoculated by dipping, but not by vacuum-infiltration, indicating involvement of Fir1 in pre-invasion immunity. RNA-seq analysis detected fewer differentially expressed genes in fir1 mutants and altered expression of jasmonic acid (JA)-related genes. In support of JA response deregulation in fir1 mutants, these plants were similarly susceptible to Pst DC3000 and to the coronatine deficient Pst DC3118 strain, and more resistant to the necrotrophic fungus Botrytis cinerea following PTI activation. These results indicate that tomato Fir1 is required for a subset of flagellin-triggered PTI responses and support a model in which Fir1 negatively regulates JA signaling during PTI activation.
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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B.
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