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Post-translational regulation of metabolism in Fumarate Hydratase deficient cancer cells

ABSTRACT: This data-set contains proteomics and phosphoproteomics of human FH-deficient UOK262 cells and their FH-complemented counterpart.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Vinothini Rajeeve

LAB HEAD: Vinothini Rajeeve

PROVIDER: PXD006693 | Pride | 2017-11-28

REPOSITORIES: Pride

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			Action	DRS
	F001314.mzid	Mzid
	F001315.mzid	Mzid
	F001316.mzid	Mzid
	F001317.mzid	Mzid
	F001318.mzid	Mzid

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1 - 5 of 36

Publications

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.

Gonçalves Emanuel E Sciacovelli Marco M Costa Ana S H ASH Tran Maxine Gia Binh MGB Johnson Timothy Isaac TI Machado Daniel D Frezza Christian C Saez-Rodriguez Julio J

Metabolic engineering 20171127

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putat ...[more]

PMID: 29191787

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ECM-enriched proteomics of human fallopian tube, fimbria and ovarian tissue

Project description:We analysed the extracellular matrix (ECM) landscape of fresh, healthy tissues from human fallopian tube (FT), fimbria (FB, the tissue of origin of serous tubal intraepithelial lesions) and ovarian tissue (OV). The aim was to identify differentially expressed matrix proteins between FB and FT or OV which may promote the neoplastic transformation of serous tubal intraepithelial lesions (STICs) into high-grade serous ovarian cancer, HGSOC, and metastasis from the FB to the OV.

2022-06-20 | PXD023912 | Pride

Fumarate hydratase orchestrates hepatic steatosis via ULK1 mediated lipophagy

Project description:Hepatic lipid homeostasis is coordinated by various metabolic pathways, such as lipogenesis, lipid uptake, storage, and oxidation. However, the underlying mechanism that orchestrates metabolic crosstalk remains unclarified. Herein, we demonstrated that fumarate hydratase (FH) functioned as an indispensable adaptor governing mitochondria metabolism and lipid droplets (LDs) degradation. Hepatic FH overexpression prevented hepatic steatosis in normal mice and ob/ob mice without interfering mitochondrial lipid oxidation and lipogenesis. Strikingly, we found that FH selectively activated lipophagy-mediated LDs lipidolysis. Mechanistically, FH interacted with ULK1 and stabilized ULK1 through preventing its ubiquitination and degradation, resulting in lipophagy activation and the elimination of hepatic lipid accumulation. Meanwhile, hepatic ULK1 deficiency abrogated the protective effects in FH-overexpressing mice. Also, we clarified that the interaction between FH and ULK1 occurred in cytoplasm, but not in mitochondria. Cytoplasmic FH was sensitive to lipids and downregulated without affecting mitochondrial FH in vivo. Moreover, the FH-ULK1 axis was identified closely associated with hepatic steatosis in human patients. Taken together, our research demonstrates a “two-side” insight of FH on hepatic lipid metabolism and provides a promising strategy for fatty liver treatment.

2024-02-26 | GSE256510 | GEO

Fumarate induces vesicular release of mtDNA to drive innate immunity

Project description:Fumarate Hydratase (FH) is an enzyme of the Tricarboxilic Acid Cycle (TCA) that catalyzes the conversion of fumarate into malate. In the last decade, studies have revealed FH as a bona fide tumour suppressor whose mutations cause Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate. Yet, whilst the long-term consequences of FH loss have been extensively described, the acute response to FH loss has not been investigated due, in part, to the lack of a suitable model. Here, we generated a new inducible mouse model to investigate the chronology of the murine homologue of FH, Fh1, loss in the adult kidney.

2023-02-17 | GSE183745 | GEO

Characterising early phosphorylation events upon HER2 protein overexpression

Project description:HER2 transduced cells which we will refer to as HER2-DOX –. These cells are 99% GFP positive (i.e., 99% cells have HER2 transduced, un-induced). As a control, we had GFP empty vector transduced MCF10A cells (95% have GFP transduced). Both cell types in triplicates. We had 4 time-points 0h, 30 mins, 4hours, and 7 hours (time duration for which HER2 will be induced). DOX was added to the GFP-MCF10A cells as a control. Only 1ug/ml of DOX was be used.

2023-01-23 | PXD034105 | Pride

Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

Project description:Nalm-6 cells co-cultured with 3T3-L1 adipocytes or pre-adipocytes were subjected to quantitative LC-MS/MS phosphoproteomic analysis at two timepoints (+24h and +72h) to determine dynamics of cell signalling. Two independent biological replicates were analysed per condition.

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BRAF mutations disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mouse and humans

Project description:Germline mutations in BRAF and other components of the Mitogen-Activated Protein Kinase (MAPK) pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harboring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAFp.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression in cell cycle inhibitors, cell growth arrest and apoptosis but not tumour formation. Our findings show a critical role for BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans

2020-11-17 | PXD018190 | Pride

Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth

Project description:A common limitation of cancer treatments is chemotherapy resistance. We have previously identified a molecular mechanism where chemotherapy resistance is regulated by endothelial cells. Endothelial cell specific knockout of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. Our current study addresses the kinase dependent component of endothelial cell FAK sensitisation to the DNA damaging chemotherapeutic drug doxorubicin. FAK is recognised as a therapeutic target in tumour cells, leading to the development of a range of inhibitors, the majority being ATP competitive kinase inhibitors. We demonstrate that specific inactivation of the FAK kinase domain in endothelial cells of blood vessels in established subcutaneous B16F0 tumours sensitises melanoma cells to doxorubicin. Tumour growth was reduced in response to doxorubicin treatment in FAK kinase-dead but not in wild-type mice. Furthermore, we demonstrate that doxorubicin reduces perivascular proliferation, enhances apoptosis and DNA-damage in endothelial cell FAK kinase dead tumours. When we treated human pulmonary microvascular endothelial cells with the FAK kinase inhibitors defactinib, PF-562,271 and PF-573,228 in combination with doxorubicin, we observed a reduction in cytokine levels, implying a possible mechanism for FAK kinase domain in chemosensitisation. Together, these results confirm the role of the kinase domain of EC-FAK in chemosensitising tumour cells to doxorubicin.

2021-11-02 | PXD019728 | Pride

Multi-Omics Analysis and Molecular Subtypes Provide Potential Therapeutic Implications in Fumarate Hydratase-deficient Renal Cell Carcinoma

Project description:Conducting an in-depth exploration of the multi-omics landscape of Fumarate Hydratase (FH)-deficient renal cell carcinoma (RCC), the study aimed to unravel the intricate molecular mechanisms underlying this rare and aggressive form of renal cancer. Analyzing 126 patients with FH-deficient RCC, we identified distinct variant spectrum of FH gene, with truncating mutation correlated with adverse prognostic factors and a worse response to immune checkpoint blockade. The identification of three molecular subtypes with diverse clinical/genomic characteristics and varying response to systemic treatment further enriched the understanding of the heterogeneous tumor microenvironment (particularly immune-related) in FH-deficient RCC, and suggested potential therapeutic targets. These findings offer a basis for molecular stratification, shedding light on the tailored therapeutic strategies in improving treatment response of FH-deficient RCC.

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Transcription profiling of human fibriods vs. normal myometrium with mutated or wild type fumarate hydratase (FH) gene reveals distinct expression profiles in fumarate-hydratase-deficient uterine fibroids.

Project description:A series of gene expression measurements of normal myometrium and uterine fibroids with mutated or wild-type fumarate hydratase (FH) gene.

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