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Microarray characterization of Vhl; Vhl, Hif1a; Vhl, Hif2a and Vhl, Hif1a, Hif2a deficient primary kidney cells

ABSTRACT: To unravel the potential cooperative roles of oxygen-regulated signaling pathways; von Hippel-Lindau (VHL) tumor suppressor protein and hypoxia-inducible factor (HIF) transcription factors, we have generated mutant mice with; Vhlh, Vhlh/Hif1α, Vhlh/Hif2α and Vhlh/Hif1α/Hif2α gene alleles floxed. Subsequently primary kidney cells were isolated, cultured and infected with Adenoviruses bearing either Cre/GFP or GFP expression only. Agilent cDNA microarrays were utilized to compare the gene expression profiles of the kidney epithelial cells from aforementioned cell cultures to gain insight about the molecules and signaling pathways that drive aberrant cellular proliferation in clear cell renal cell carcinoma (ccRCC).

ORGANISM(S): Mus musculus

PROVIDER: GSE75745 | GEO | 2016/01/08

SECONDARY ACCESSION(S): PRJNA305267

REPOSITORIES: GEO

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Microarray characterization of Vhl; Vhl, Hif1a; Vhl, Hif2a and Vhl, Hif1a, Hif2a deficient primary kidney cells

Project description:To unravel the potential cooperative roles of oxygen-regulated signaling pathways; von Hippel-Lindau (VHL) tumor suppressor protein and hypoxia-inducible factor (HIF) transcription factors, we have generated mutant mice with; Vhlh, Vhlh/Hif1Î±, Vhlh/Hif2Î± and Vhlh/Hif1Î±/Hif2Î± gene alleles floxed. Subsequently primary kidney cells were isolated, cultured and infected with Adenoviruses bearing either Cre/GFP or GFP expression only. Agilent cDNA microarrays were utilized to compare the gene expression profiles of the kidney epithelial cells from aforementioned cell cultures to gain insight about the molecules and signaling pathways that drive aberrant cellular proliferation in clear cell renal cell carcinoma (ccRCC). 24 independent biological samples from 4 genetic experimental conditions were hybridized in two- color format on 13 Mouse GE 4x44K v2 Microarray Kit (Design ID 026655) arrays. Eventual dye specific hybridization effects were controlled with dye swap on biological replicates. For an each experimental condition 3 arrays were use, except of one where 4 arrays were used (one sample combination in repetition with a dye swap). For the final analysis the gene expression levels were dye effect corrected and values for biological replicates were averaged to obtain a matrix with gene expression levels for 4 independent biological (1. Vhlh-/-, 2. Vhlh-/-/Hif1Î±-/-, 3. Vhlh-/-/Hif2Î±-/- and 4. Vhlh-/-/Hif1Î±-/-/Hif2Î±-/-) conditions.

2016-01-08 | E-GEOD-75745 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

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2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

2013-09-30 | GSE47582 | GEO

Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease

Project description:To establish the role of proximal tubular hypoxia in diabetic kidney disease, we use a mouse line with a specific deletion of von-Hippel-Lindau (VHL) in the proximal tubule and treat them with streptozotocin (STZ) to induce a type I diabetes mellitus. 10 weeks after induction of diabetes mellitus samples were collected.

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USP37 Promotes Deubiquitination of HIF2a in Kidney Cancer

Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by a loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor (including HIF1 and HIF2). HIF2 was previously reported to be one of the major oncogenic drivers in ccRCC, however its therapeutic targeting remains challenging. Here we performed a deubiquitinase (DUB) cDNA library binding screen and discovered that USP37 is a DUB that binds HIF2 and promotes HIF2 deubiquitination. As a result, USP37 promotes HIF2 protein stability in an enzymatically dependent manner and depletion of USP37 leads to HIF2 downregulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, 2-D colony formation as well as 3-D anchorage independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential new therapeutic target in ccRCC.

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HIF1α/HIF2α-miR210-3p network promotes glioblastoma proliferation and tumorigenesis through EGFR-PI3K/AKT signaling pathway with a positive feedback

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RNAseq transcriptome analysis of THP-1 macrophages activated by VHL-deficient kidney tubule cells

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.

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Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease

Project description:Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease

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786-O and 786-VHL in EMCV study

Project description:786-0 is a cell line derived from a clear cell renal carcinoma. Previous studies have shown that the 786-O cell line harbors an inactivating mutation in the von-Hippel Lindau (VHL) gene. Mutations in the VHL gene occur in the majority of sporadic clear cell renal cell. To determine how inactivation of the VHL affects cellular functions, we created a derivative of 786-0, which we call 786-VHL in which a functional allele of VHL has been introduced back into the 786-O cell line.

2010-06-10 | GSE22256 | GEO

Genome-wide mapping of Hif-1Î± binding sites in zebrafish [ChIP-seq]

Project description:Analysis of the binding sites of Hif-1Î± in both wild-type and von Hippel Lindau mutant zebrafish lines at 4dpf by ChIP linked next generation sequencing. The von Hippel Lindau mutant displays a systemic hypoxic response under normoxic conditions. Results show the extent of Hif-1Î± binding to the genome, and provide a basis for analysis of the transcriptional response to genetically induced hypoxia in zebrafish. Analysis of the DNA binding sites of Hif-1Î± in both wild-type and von Hippel Lindau mutant zebrafish lines at 4dpf. The von Hippel Lindau mutant displays a systemic hypoxic response under normoxic conditions. Results show the extent of Hif-1Î± binding to the genome, and provide a basis for analysis of the dependency of the transcriptional response on Hif-1Î± in conditions of genetically induced hypoxia in zebrafish.

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