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Expression profiling of thymic lymphomas from p53 mutant (R270H) mice with varying HIF levels

ABSTRACT: Expression profiling of thymic lymphomas derived from HIF1a+/+, p53R270H/R270H; HIF1a+/-, p53R270H/R270H; and HIF1aKI/+, p53R270H/R270H mice. HIF1a and HIF2a share a high degree of sequence homology, but recent work has shown that the two a subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFa subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2a expression and Hif1a+/- mice to homozygotes for the R270H mutation in p53. Heterozygosity for Hif1a significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1a levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. Keywords: genetic modification, disease state analysis

ORGANISM(S): Mus musculus

PROVIDER: GSE14336 | GEO | 2009/01/12

SECONDARY ACCESSION(S): PRJNA111517

REPOSITORIES: GEO

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Expression profiling of thymic lymphomas from p53 mutant (R270H) mice with varying HIF levels

Project description:Expression profiling of thymic lymphomas derived from HIF1a+/+, p53R270H/R270H; HIF1a+/-, p53R270H/R270H; and HIF1aKI/+, p53R270H/R270H mice. HIF1a and HIF2a share a high degree of sequence homology, but recent work has shown that the two a subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFa subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2a expression and Hif1a+/- mice to homozygotes for the R270H mutation in p53. Heterozygosity for Hif1a significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1a levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. Keywords: genetic modification, disease state analysis Thymic lymphoma tissue was preserved at the time mice were sacrificed. 4-5 samples from each of 3 genotypes (HIF1a+/-, p53R270H/R270H, HIF1aKI/+; p53R270H/R270H; and HIF1a+/+, p53R270H/R270H) were then used for microarray analysis to identify differences in gene expression that could account for changes in tumor onset and incidence.

2009-01-12 | E-GEOD-14336 | biostudies-arrayexpress

Transcriptome alterations in prostates from Trp53 R270H mutant mice following irradiation

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2022-03-02 | GSE130440 | GEO

Mutant p53 R270H induces invasion and metastasis of mouse intestinal tumor organoids through gain-of-function mechanism

Project description:Apc(D716) mutant mice develop benign intestinal adenoma, while Apc(D716) and p53 R270H compound mutant mice develop invasive adenocarcinoma in the intestine. We examined expression profile of tumor-derived organoids using Apc(D716), Apc(D716) p53 Null, Apc(D716) p53 R270H mutant mice by RNA sequencing, and identified mutant p53-induced gene set.

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RNA expression profiles from HUVECs overexpressing adenovirally delivered HIF1a and HIF2a proteins

Project description:RNA-Seq analysis was performed from human umbilical vein endothelial cells exposed to constitutively active HIF1a and HIF2a overexpression

2018-05-16 | GSE98060 | GEO

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

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DAOY-NERT2 Notch/Hypoxia Transcriptome Analysis

Project description:Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2a, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2a by Notch under normoxic conditions leads to elevated HIF2a protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma and renal cell carcinoma cell lines. The elevated level of HIF2a protein was in certain tumor cell types accompanied by down-regulation of HIF1a protein levels, indicating that high Notch signaling may drive a HIF1a-to-HIF2a switch. At the transcriptome level, the presence of HIF2a was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2a expression was knocked down by HIF2a siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2a, which may be important for future cancer therapies.

2018-04-19 | GSE113353 | GEO

DAOY-Notch1/Notch2 knockout: transcriptome comparison

Project description:Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2a, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2a by Notch under normoxic conditions leads to elevated HIF2a protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma and renal cell carcinoma cell lines. The elevated level of HIF2 protein was in certain tumor cell types accompanied by down-regulation of HIF1a protein levels, indicating that high Notch signaling may drive a HIF1a-to-HIF2a switch. At the transcriptome level, the presence of HIF2a was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2a expression was knocked down by HIF2a siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2a, which may be important for future cancer therapies.

2018-04-28 | GSE113753 | GEO

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Project description:Expression profiling of thymic lymphomas from p53 mutant (R270H) mice with varying HIF levels

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The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [ChIP-seq]

Project description:Acute myeloid leukemia (AML) is characterized by an accumulation of aberrant myeloid cells arrested at different stages of differentiation. Therapeutic approaches that prompt AML blasts to differentiate represent an attractive opportunity in the landscape of AML therapies, as they aim to induce terminal maturation and leukemia debulking without intensive cytotoxic treatments. In the present study, we investigate the involvement of HIF1a and HIF2a transcription factors in AML pathogenesis, and position HIF2a as a novel regulator of the AML differentiation block. We performed a comparative analysis of HIF1a and HIF2a function in AML cell lines via their inhibition with genetic or pharmacological strategies and found that both factors promote AML proliferation and clonogenicity. Importantly, specific inhibition of HIF2a provokes AML cell differentiation in cell lines and patient-derived xenograft (PDX) models. Additionally, we demonstrate that HIF2a is positively regulated by the pro-differentiation agent all-trans retinoic acid (ATRA), and its inhibition cooperates with ATRA in triggering AML cell differentiation. In conclusion, we report evidence of a new role of HIF2a in the pathogenesis of AML, and we propose that HIF2a inhibition may open new therapeutic avenues for AML treatment by licensing AML differentiation and synergizing with ATRA towards leukemia exhaustion.

2023-08-10 | GSE228757 | GEO

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

Project description:WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated by genetic crossing. In these mice, Pten is deleted and a R270H p53 mutation in the DNA binding domain is induced upon expression of Cre recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, various bioinformatics methods, high-throughput (HTP) FDA-drug screen as well as orthotopic injection to quantify tumor initiating cells (TICs) and tail-vein injection to identify lung-metastasis. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other modles of mouse mammary tumors 2 types of Pten deletion plus p53-R270H mutation tumors (spindle and poorly differentiated) was compared with MMTV-Neu, Spindle Pten-p53-deficient tumors, and wild-type mammary gland cells.

2015-12-15 | E-GEOD-75989 | biostudies-arrayexpress

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