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Expression data from KEAP1 overexpression and NRF2 siRNA knockdown of A549 NSCLC cell

ABSTRACT: KEAP1 overexpressed and NRF2 siRNA knockdown A549 NSCLC cells were used to identify downstream genes of NRF2 pathway separately and by combinatorial analysis. We used triplicate microarrays of transfected A549 cells with mKeap1-GFP for overexpression, siRNAs targeting NRF2 for knockdown and siGFP as control respectively. As a result, we identified several genes which are involved in cancer metabolic functions in these cells. We used microarrays to identify the gene downregulated in both KEAP1 overexpressed and NRF2 siRNA knockdown A549 NSCLC cells and found a subset of downregulated genes which are involved in metabolic functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94393 | GEO | 2017/08/02

SECONDARY ACCESSION(S): PRJNA369558

REPOSITORIES: GEO

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Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

Project description:Keap1 overexpressed and Nrf2 depleted CL1-5 cells were used to identify genes regulated by Keap1/Nrf2 axis-dependent gene regulations We used microarrays to detail the global programme of gene expression underlying metastasis and identified distinct classes of Keap1/Nrf2-regulated genes during this process. CL1-5 cells stably expressed Keap1 expressing construct and Nrf2-specific shRNA were analyzed compared to control cells

2015-03-04 | E-GEOD-66473 | biostudies-arrayexpress

Homo sapiens

Project description:Expression data from KEAP1 overexpression and NRF2 siRNA knockdown of A549 NSCLC cell

| PRJNA369558 | ENA

Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

2015-03-04 | GSE66473 | GEO

Nrf2 Mediates RNA Splicing Through Physical Association with the Survival Of Motor Neuron (SMN) Complex and Transcriptional Activation of the SMN1 Gene In Non-Small Cell Lung Cancer

Project description:The nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) signal pathway is frequently deregulated in human cancers. The critical functions of NRF2 other than transcriptional activation in cancers remain largely unknown. Here, we uncovered a previously unrecognized role of Nrf2 in RNA splicing via regulating survival of motor neuron protein (SMN). Here, we performed next-generation high throughput global RNA-sequencing of siNrf2-C27 and siGFP-C5, which are stable NRF2-knockdown and control cell lines derived from A549 NSCLC cells, respectively To investigate whether NRF2 plays any role in RNA splicing.

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Keap1 knockdown in melanocytes induces cell proliferation and survival via HO-1-associated β-catenin signaling

Project description:Nrf2-Keap1 signaling pathway protects cells against photo-oxidative stress. Yet in recent works, its role in melanogenesis together with cell protection functions against oxidative stress has been gaining interest. However, its effect on melanogenesis still has contradictory results from different studies. The aims of our study were to investigate the effect of Keap1 silencing in melanocyte on melanogenesis and its associated mechanism. Primary human epidermal melanocytes and melan-a cell line were used for this experiment. RNA sequencing was done to identify genes involved in melanocyte biology using Keap1 knockdown through siRNA techniques. And melanogenesis and the expression of melanogenesis-associated molecules were evaluated in Keap1 silenced melanocyte to examine the effects of Keap1 on melanogenesis, melanocyte growth, and related pathways. RNA-sequencing data revealed that Keap1 knockdown in primary human epidermal melanocytes (PHEMs) induced cell survival-related gene expression. Additionally, siRNA-mediated inhibition of Keap1 led to upregulation of MITF and melanogenesis-associated molecules along with Nrf2 activation in PHEMs. HO-1, a major gene that is upregulated in RNA-sequencing using Keap1-silenced PHEMs, protected melanocytes against H2O2-induced cell death and upregulated MITF and β-catenin expression. Further, increased expression of melanogenesis-associated molecules after Keap1 silencing was validated to occur through HO-1-associated β-catenin activation in a Keap1 and HO-1 double knockdown experiment. This work suggests that Keap1 silencing in melanocytes induced melanogenesis and the expression of melanogenesis-associated molecules through HO-1-associated β-catenin activation. Keap1 downregulation in melanocytes is important for cell proliferation and survival.

2018-01-20 | GSE93895 | GEO

Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane treated human breast epithelial cells

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2011-04-22 | E-GEOD-28813 | biostudies-arrayexpress

Comparison of gene expression profiles among Nrf1 liver-specific conditional knockout, Nrf2 knockout and Keap1 knockdown mice.

Project description:To identify Nrf1-dependent and Nrf2-dependent genes in the liver, we examined the gene expression profiles of Nrf1 Alb-CKO, Nrf2 knockout and Keap1 knockdown mouse livers by microarray analyses. Total RNAs from Nrf1dN/-::Alb-Cre, Nrf1dN/+, Nrf2-/-, Nrf2+/+, Keap1KD/- and Keap1KD/+ mouse livers were used for the microarray analyses.

2012-05-17 | E-GEOD-35124 | biostudies-arrayexpress

Identification of Nrf2-regulated genes in A549 lung cancer cells by oligonucleotide microarray

Project description:To elucidate the mechanisms by which Nrf2 regulates cell growth, we performed global gene expression profiling of A549 lung cancer cells with knockdown of Nrf2. Gene networks associated with carbohydrate metabolism and drug metabolism were significantly downregulated in Nrf2-depleted A549 cells. Gene Set Enrichment Analysis revealed significant enrichment of genes associated with carbohydrate catabolic processes, positive regulation of metabolic processes, PPP, and arachidonic acid metabolism. In summary, this analysis revealed that Nrf2 positively regulates transcription of genes that play key roles in central carbon metabolism. A549 cells were transfected with non targeting NS siRNA or siRNA targeting Nrf2. Mock transfected A549 cells were treated with transfection reagent alone. We had 3 biological replicates for each of the 3 groups. Ninty six hours post transfection, cells were lysed and total RNA was isolated.

2013-07-04 | E-GEOD-38332 | biostudies-arrayexpress

Nrf2 sequesters Keap1 preventing podosome disassembly

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

Patient-derived KEAP1 superbinder mutants stabilize KEAP1 structure and sequester NRF2 in p62-dependent clusters

Project description:Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a previous study of KEAP1 mutations observed in lung cancer, we classified 40% of the mutations as ‘superbinders’ (superbinders). These mutants bind and ubiquitylate NRF2 but do not promote NRF2 degradation. Here, we further investigated the molecular mechanism(s) driving the superbinder phenotype. BioID-based quantitative proteomic analysis of the R320Q and R470C superbinder mutations revealed increased co-complexed NRF2 without significant alteration to other KEAP1-associated proteins, including CUL3, VCP, and several ubiquitin receptors within the proteasome lid. Dynamic simulation modeling and limited proteolysis analyses suggest that superbinder mutations stabilize residues in KEAP1 that contact NRF2. In cells, KEAP1 R320Q and R470C mutants co-localize with NRF2, p62/SQSTM1 and polyubiquitin in spherical clusters that rapidly fuse and dissolve; KEAP1-NRF2 localization to these clusters requires p62. Expression of R320Q and R470C in lung cancer cells provided resistance to the reactive oxygen species-inducing drug bleomycin. We present a model wherein superbinder mutations alter the conformational dynamics of the KEAP1-NRF2 complex to alter the cycling of KEAP1 between open and closed conformations, thus inhibiting NRF2 degradation.

2018-11-07 | PXD008411 | Pride

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