Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA511867 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8370090.fastq.gz | Fastqsanger.gz | |||
| SRR8370100.fastq.gz | Fastqsanger.gz | |||
| SRR8370091.fastq.gz | Fastqsanger.gz | |||
| SRR8370101.fastq.gz | Fastqsanger.gz | |||
| SRR8370092.fastq.gz | Fastqsanger.gz |
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Project description:Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload evoked by FBXL5 ablation gives rise to oxidative stress, tissue damage, inflammation and compensatory proliferation in hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting effect of FBXL5 deficiency in the liver is also operative in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis induced by iron overload. Dysregulation of FBXL5-mediated cellular iron homeostasis was also found to be associated with poor prognosis in human HCC, implicating FBXL5 plays a significant role in defense against hepatocarcinogenesis.
2019-03-09 | GSE124370 | GEO
Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients Using Ribotag technology, from mouse ventral midbrain lysates, we isolated actively translated mRNA species from control and Transferrin receptor 1-null dopaminergic neurons. Two mouse ages were used 3 wks (early neurodegeration) 10 wks (late neurodegeneration)
2015-03-11 | E-GEOD-66730 | biostudies-arrayexpress
Project description:Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.
| S-EPMC6446870 | biostudies-literature
Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients
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Project description:Disruption of H3K36 methylation provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis
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Project description:Hematopoietic stem cells (HSCs) are maintained in the hypoxic niche so as to limit oxidative stress. Although iron is a major factor to evoke oxidative stress, the importance of cellular iron homeostasis in HSCs has been unrecognized. We now demonstrate that iron regulation mediated by FBXL5 is required for the self-renewal capability of HSCs. Conditional ablation of Fbxl5 gene in mouse HSCs resulted in cellular iron overload, leading to the reduction in the number of HSCs. Bone-marrow transplantation experiments revealed that FBXL5-deficient HSCs were unable to reconstitute the hematopoietic system as a result of stem cell exhaustion. Transcriptomic analysis showed abnormal activation of oxidative stress response as well as cell cycle in HSCs. Suppression of IRP2 activity in FBXL5-deficient HSCs restored the stem cell function, suggesting that IRP2 is potentially a novel therapeutic target of stem cell diseases such as myelodysplastic syndrome, which is associated with FBXL5 downregulation in humans.
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Project description:As a key vector for the major arthropod-borne viruses (arboviruses), such as dengue, Zika and chikungunya, control of Aedes aegypti represents a major challenge in public health. Bloodmeal acquisition is necessary for the reproduction of vector mosquitoes and pathogen transmission. Blood contains potentially toxic amounts of iron while it provides nutrients for mosquito offspring; disruption of iron homeostasis in the mosquito may therefore lead to a novel control strategies. We previously described a potential iron exporter in Ae. aegypti after a targeted functional screen of ZIP and ZnT family genes. In this study, we performed an RNAseq-based screen in an Ae. aegypti cell line cultured under iron-deficient and iron-excess conditions. A subset of differentially expressed genes were analyzed via a cytosolic iron-sensitive dual-luciferase reporter assay with several gene candidates potentially involved in iron transport. In vivo gene silencing resulted in significant reduction of fecundity (egg number) and fertility (hatch rate) for one gene, AAEL000471. Consistent with a role in iron homeostasis, ferritin expression in the midgut was reduced upon silencing of AAEL000471. Silencing of AAEL000471 also resulted in delayed/impaired excretion and digestion. Together these studies increase our understanding of gene regulatory networks controlling iron homeostasis in bloodfeeding mosquitoes, and suggest new targets for vector control based on the disruption of this critical process.
2021-04-01 | GSE160498 | GEO
Project description:The study of gene expression profile of iron homeostasis-related genes using Affymetrix GeneChips in conjunction with the pathological assessment of hepatic iron content in hepatocellular carcinoma (HCC) samples offers a new strategy to understand the role of hepatic iron overload in hepatocarcinogenesis.
2007-01-10 | E-MEXP-84 | biostudies-arrayexpress
Project description:The Endoplasmic Reticulum–Mitochondria Encounter Structure (ERMES) is a protein complex that tethers the two organelles and creates the physical basis for communication between them. ERMES functions in lipid and calcium exchange between the ER and mitochondria, mitochondrial protein import and maintenance of mitochondrial morphology and genome. Here we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of ERMES known roles in calcium regulation, phospholipid biosynthesis or mitochondrial biology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our study reveals that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels.
2017-06-20 | GSE99499 | GEO
Project description:Disruption of H3K36 methylation provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis (Spatial Transcriptomics)
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