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Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggesssive Murine Hepatoblastomas

ABSTRACT: Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggesssive Murine Hepatoblastomas

PROVIDER: PRJNA662245 | ENA |

REPOSITORIES: ENA

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Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggesssive Murine Hepatoblastomas

Project description:The pediatric liver cancer hepatoblastoma (HB) often expresses mutant forms of b-catenin and dysregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing b-catenin mutants and the constitutively active Hippo effector YAPS127A. Some human HBs also express mutant forms of NFE2L2/NRF2 (NFE2L2), a bHLH transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis in a context- and time-dependent manner. We show here that two patient-derived NFE2L2 missense mutants, L30P and R34P, markedly accelerate HB growth in association with diffuse cyst formation, an otherwise uncommon feature of human HB. Surprisingly, we found that any two members of the mutant b-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus providing direct evidence for NFE2L2’s oncogenicity. Each tumor group showed distinct features but shared a similarly deregulated set of 22 transcripts, 10 of which perfectly correlated with survival in human HBs. 17 transcripts also correlated with survival in multiple cancers. One of the most deregulated transcripts encoded Serpin E1, a serine protease inhibitor with roles in fibrinolysis, tumor growth and extracellular matrix formation. The combination of mutant b-catenin-YAPS127A-Serpin E1 neither accelerated tumor growth nor generated cysts but did promote large-scale necrosis that was often associated with the cysts seen in mutant b-catenin-YAPS127A-L30P/R34P tumor, albeit on a lesser scale. These findings establish the direct oncogencity of NFE2L2 mutants and identify key transcripts, including Serpin E1, that impact tumor growth and other HB features.

2021-05-20 | GSE157623 | GEO

Analysis of NFE2L2 (NRF2) binding to chromatin in primary human keratinocytes

Project description:Analysis of NFE2L2 (NRF2) binding to chromatin in primary human keratinocytes

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Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas.

Project description: Not available

| S-EPMC8102178 | biostudies-literature

Gene expression profiling of neutrophils and whole lung tissue from wildtype and Nrf2 null (Nfe2l2-/-) mice during S. pneumoniae pneumonia [neutrophils]

Project description:The transcription factor Nrf2 (gene symbol Nfe2l2) regulates the transcriptional response to oxidative stress and plays a critical protective role in the lungs. These studies tested the role of Nrf2 during pneumonia induced by Streptococcus pneumoniae (SP) at 24 hours in mice and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils.

2016-09-09 | GSE83613 | GEO

Gene expression profiling of neutrophils and whole lung tissue from wildtype and Nrf2 null (Nfe2l2-/-) mice during S. pneumoniae pneumonia [whole lung]

2016-09-09 | GSE83612 | GEO

Analysis of NFE2L2 (NRF2) binding to chromatin in primary human keratinocytes

Project description:Analysis of NFE2L2 (NRF2) binding to chromatin in primary human keratinocytes

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Comparison of the transcriptomic impact of NRF2 depletion with that of NUAK1 depletion in SW480 colorectal cancer cells

Project description:The intent of the experiment is to determine how much of NRF2 (NFE2L2)-dependent transcription requires NUAK1 upstream. SW480 cells were transfected with siRNA targeting either NRF2, NUAK1 or non-targeting control, and harvested for analysis by RNA-SEQ 48hrs after transfection. mRNA was analysed by Illumina paired-end RNA-SEQ

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Identification of Novel NRF2-Regulated Genes by ChIPSeq

Project description:Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to DNA-regulatory sequences near stress responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted ChIP-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high-confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRAhas implications for response to retinoid treatments and adipogenesis. In mouse 3T3-L1 cells SFN treatment affected Rxra expression early in adipogenesis and knockdown of Nrf2 delayed Rxra expression, both leading to impaired adipogenesis. ChIP-Seq analysis of NRF2 binding sites in human lymphoblastoid cells treated with sulforaphane or vehicle

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Transgenic expression of Nrf2 in the mouse

Project description:NFE2L2, nuclear factor, erythroid 2 like 2 (Nrf2), is a transcription factor that protects cells through maintaining a homeostatic redox state during stress. Constitutive expression of Nrf2 (CaNrf2-TG) was previously shown to be pathological to the heart over time. We tested a hypothesis that the cardiac-specific expression of full length Nrf2 (mNrf2-TG) would moderately increase the basal antioxidant defense, triggering a pro-reductive environment leading to adaptive cardiac remodeling.

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A Conditional Mouse Expressing a Tumor-derived Mutation in the NRF2 Transcription Factor Displays Hyperplasia of the Upper Gastrointestinal Tract and Decreased White Adipose Fat

Project description:Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Whereas NRF2 deficiency results in hypersensitivity to a variety of stressors, its aberrant activation contributes to several cancer types, most commonly squamous cell carcinomas of the oesophagus, oral cavity, bladder and lung. Between 10-35% of patients with squamous cell carcinomas display hyperactive NRF2 signaling, harboring activating mutations and copy number amplifications of the NFE2L2 oncogene or inactivating mutations or deletions of KEAP1 or CUL3, which co-complex to ubiquitylate and degrade NRF2 protein. To better understand the role of NRF2 in tumorigenesis and more broadly in development, we engineered the endogenous Nfe2l2 genomic locus to create a conditional mutant LSL-Nrf2E79Q mouse model. The NRF2E79Q mutant protein does not undergo KEAP1/CUL3-dependent degradation, resulting in its constitutive activity. The E79Q mutation is also one of the most commonly observed NRF2-activating mutations in human squamous cancers. Expression of NRF2E79Q protein in keratin 14 (Krt14)-positive murine tissues resulted in a stunted body axis, decreased weight, decreased adipocyte size, and hyperplasia of squamous cell tissues of the tongue, forestomach, and oesophagus. RNAseq profiling and follow-up validation studies of cultured Nrf2E79Q murine esophageal epithelial cells revealed known and novel NRF2-regulated transcriptional programs, including genes associated with squamous cell carcinoma (e.g. Myc), lipid and cellular metabolism (Hk2, Ppard), and growth factors (Areg, Bmp6, Vegfa). These data suggest that in addition to decreasing adipogenesis, KRT14 restricted NRF2 activation leads to hyperplasia of the oesophagus, forestomach and tongue, but notably is not sufficient to drive formation of squamous cell carcinoma.

2020-06-23 | GSE141311 | GEO

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