The oncogenic action of NRF2 depends on de-glycation by Fructosamine-3-kinase (FN3K)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA550119 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9409840.fastq.gz | Fastqsanger.gz | |||
| SRR9409850.fastq.gz | Fastqsanger.gz | |||
| SRR9409841.fastq.gz | Fastqsanger.gz | |||
| SRR9409842.fastq.gz | Fastqsanger.gz | |||
| SRR9409843.fastq.gz | Fastqsanger.gz |
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Project description:The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K) - a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.
2019-07-08 | PXD014334 | Pride
Project description:We show that NRF2 activation drives hepatocellular carcinoma development in vivo. Moreover, NRF2 undergoes glucose dependent modification called glycation and requires the de-glycating enzyme FN3K to maintain NRF2' oncogenic functions.
2019-06-22 | GSE133160 | GEO
Project description:The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.
| S-EPMC6693658 | biostudies-literature
Project description:WGS and RNA-seq data for Nrf2 study
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Project description:Nrf2 is a transcription factor playing an essential role in stress response. A knowledge of the significance of Nrf2 in cell function has not, as yet, reached out beyond transactivation of gene expression. This paper shows that GDF-15 and SDF-1-induced angiogenesis strongly depends on Nrf2 presence, but is not related to its transcriptional activity. We propose, that Nrf2 serves as a protein restraining Keap1, its known transcriptional repressor. Deficiency of Nrf2 protein available for Keap1 leads to overabundance of RhoGAP1, the protein regulating Cdc42 activity, and impairs podosome assembly, thereby indisposing actin rearrangements, preventing migration and angiogenesis. These activities can be rescued by concomitant deletion of RhoGAP1 or Keap1. We suggest that a new Nrf2 function of a Keap1 scavenger implies revising the established murine model of Nrf2 deficiency as a transcriptional knock out (tKO) mouse. The N-terminal fragment of Nrf2, containing Neh2 domain binding Keap1, is present in these animals. Thus, regarding the function of Nrf2 as a protein sequestering Keap1, both published and unpublished data on Nrf2-Keap1 duet may gain new interpretation.
2018-11-28 | PXD009161 | Pride
Project description:Glycation is a covalent protein modification that accumulates in the cellular environment. Histone proteins are particularly susceptible to glycation due to their extremely long half-lives and nucleophilic disordered tails. Here, we performed ATAC-seq on 293T cells cultured in the presence or absence of 0.5mM methylglioxal, a reactive glycolytic intermediate, for 12 hours. We demonstrate that methylglioxal treatment is associated with changes in histone occupancy and chromatin architecture globally.
2019-02-14 | GSE121252 | GEO
Project description:Nrf2-regulated mRNAs are known; however, no Nrf2-regulated miRs have been identified miR microarray analysis from total RNA samples was performed to test which miRs are regulated by Nrf2 Total RNA from skin of mice with constitutively active Nrf2 (CMV-caNrf2), dominant-negative Nrf2 (dnNrf2), and correcponding control littermates (K5Cre(wt) for CMV-caNrf2 and wt for dnNrf2)
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Project description:Non-enzymatic reactions in glycolysis lead to the accumulation of methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity and aging-associated pathologies. A combination of nicotinamide, lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low), was identified to lower glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Administration of Gly-Low reduced food consumption, lowered body weight, improved insulin sensitivity, and increased survival in both leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Unlike caloric restriction, Gly-Low modulated hypothalamic signaling by upregulating mTOR pathway signaling to inhibit ghrelin-mediated hunger response. Gly-Low also slowed hypothalamic aging and increased survival when administered as a late-life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary caloric restriction and reducing glycation.
2025-02-28 | GSE234483 | GEO
Project description:We performed bulk transcriptomic analysis to examine how glycation-modified collagen further impacts the function of meningeal fibroblasts. We preprocessed raw data to align bulk RNA-seq using STAR (detailed in Experimental Section) and identified differentially expressed genes (DEGs), especially ECM-related gene sets.
2022-10-26 | GSE216298 | GEO
Project description:Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic β-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Chromatin occupancy of Nrf2 under CDDO-Im-treated condition were generated by deep sequencing, in dupliplicate
2016-04-06 | E-GEOD-78780 | biostudies-arrayexpress