Hif-1alpha deletion leads to adverse treatment efficacy in a mouse model of MLL-AF9 driven AML
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ABSTRACT:
PROVIDER: PRJNA489376 | ENA |
REPOSITORIES: ENA
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Project description:This report explores the effect of Hif-1alpha deletion, using a conditional mouse model, together with standard chemotherapy regimen to evaluate leukemia stem cell (LSC) targeting in a murine model of MLL-AF9 driven acute myeloid leukemia (AML). This study reveals that Hif-1alpha-deleted leukemias displayed a faster disease progression after chemotherapy.
2019-01-23 | GSE119484 | GEO
Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci. Comparison of HIF-1alpha ChIP-chip and HIF-2alpha ChIP-chip to map HIF-1- and HIF-2-specific gene targets across the genome.
2013-11-05 | E-GEOD-43108 | biostudies-arrayexpress
Project description:An oxygen stable form of HIF-1alpha was overexpressed in the hearts of mice, under tet-off control. Bi-allelic transgenic mice were created by crossing alpha-MHC promoter/tet transactivating protein expressing mice with tet responsive element promter/stable HIF-1alpha protein expressing mice. Mice were either, maintained on Doxycycline (inhibiting the expression of the HIF-1alpha transgene) or removed from doxycycline (inducing expression) for one or three days.
2010-05-15 | E-GEOD-12673 | biostudies-arrayexpress
Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci.
2013-11-05 | GSE43108 | GEO
Project description:We reported that HAUSP (USP7) deubiquitinase interacts with and deubiquitinates HIF-1α to increase its stability and functions. HAUSP, HIF-1alpha and CBP could form a complex to regulate histone modification and gene transcription
2016-01-13 | GSE76770 | GEO
Project description:An oxygen stable form of HIF-1alpha was overexpressed in the hearts of mice, under tet-off control.
2008-12-02 | GSE12673 | GEO
Project description:Hypoxia and inflammation are key factors for colorectal cancer tumorigenesis. The colonic epithelium belongs to the tissues with the lowest partial pressure of oxygen in the body, and chronic inflammation is associated with an increased chance to develop colon cancer. How the colonic epithelium responds to hypoxia and inflammation during tumorigenesis remains to be elucidated. Here we show, that murine colon adenocarcinoma cells with attenuated response to hypoxia, due to a knock-down (KD) of HIF-1alpha produce smaller and less hypoxic tumors in an orthotopic mouse model when compared to tumors induced with control cells. HIF-1alpha-KD tumors showed more functional perfused vasculature associated with increased levels of vessel-stabilizing factors and reduced levels of pro-angiogenic factors, including extracellular matrix protein Cyr61/CCN1. Intratumoral injection of Cyr61 in HIF-1alpha-KD tumors revealed an in increased vessel permeability and tumor hypoxia. Further bioinformatics analysis identified a possible interaction between HIF-1alpha and TRAF6, an upstream effector of the NF-kappaB pathway that was confirmed by co-immunoprecipitation in MC-38 and CT26 colon adenocarcinoma cells. Down-regulation of TRAF6 resulted in virtual abrogation of orthotopic tumor growth. Subcutaneous TRAF6-KD tumors were smaller and contained reduced vessel size and differently polarized macrophages. These data demonstrate that the tumor cell response to increased hypoxia in the colon leads to promotion of non-functional angiogenesis, regulated by both hypoxia and TRAF6 pathways.
2020-11-09 | GSE155104 | GEO
Project description:Human renal cell carcinomas (RCC) have differential expression of HIF-1alpha and HIF-2alpha, depending on VHL genotype and other events. Here, we have divided a series of RCC samples for HIF-alpha expression and VHL genotype, in order to define differentially expressed genes Keywords: Patient Sample Study A total of 57 frozen RCC samples were stained for HIF-1alpha and HIF-2alpha, and genotyped for VHL. 5 VHL WT/HIF-negative, 8 VHL-deficient/HIF-1alpha+/HIF-2alpha+ and 8 VHL-deficient/HIF-2alpha+ tumors were selected for microarray
2008-12-27 | E-GEOD-11904 | biostudies-arrayexpress
Project description:Human renal cell carcinomas (RCC) have differential expression of HIF-1alpha and HIF-2alpha, depending on VHL genotype and other events. Here, we have divided a series of RCC samples based on HIF-alpha expression, in order to examine levels of genomic DNA aberration. Keywords: Patient Sample Study A total of 57 frozen RCC samples were stained for HIF-1alpha and HIF-2alpha, and genotyped for VHL. 10 VHL-deficient/HIF-1alpha+/HIF-2alpha+ and 11 VHL-deficient/HIF-2alpha+ tumors were selected for array CGH.
2008-12-27 | E-GEOD-13282 | biostudies-arrayexpress
Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1alpha and HIF-2a transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1a as an inhibitor and HIF-2a as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1a and HIF-2a are required for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1alpha regulates glycolysis while HIF-2a regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2a-deficient tumours were characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlated with altered immune microenvironment in human ccRCC. These studies reveal an oncogenic role of HIF-1alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1alpha and HIF-2a activities can affect different aspects of ccRCC biology and disease aggressiveness.
2020-05-22 | GSE150983 | GEO