Hypoxic changes in gene expression: effect of vhl and p53 genotype
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE4186 | GEO | 2006/03/07
SECONDARY ACCESSION(S): PRJNA95151
REPOSITORIES: GEO
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Project description:The CH1 (TAZ) domain of the transcriptional coactivators p300 and CBP has been reported to interact with the transcription factor HIF-1alpha and this interaction is thought to be critical for HIF-1alpha target gene expression in response to hypoxia. To determine the requirement for the CH1 domain in hypoxia-responsive gene expression, primary mouse embryonic fibroblasts (MEFs) were generated from e14.5 C57B/6x129/Sv F2 embryos that were either wildtype or bore deletion mutations in the CH1 protein binding domains of both alleles of p300 and one allele of CBP (tri_CH1). Subconfluent MEFs were treated with 21% oxygen (normoxia) or 0.1% oxygen (hypoxia) with 5% carbon dioxide at 37 C in a humid chamber for 6hrs. At the start of treatment, medium was removed and replaced with medium (DMEM+10% FBS+pen-strep+ l-glu) that had been preequilibrated overnight in normoxia or hypoxia as appropriate. Immediately after treatment, cells were lysed in Trizol for RNA extraction. Experiment Overall Design: 4 samples: two genotypes (1 control, 1 mutant); two treatments (normoxia, hypoxia).
2008-06-12 | E-GEOD-3195 | biostudies-arrayexpress
Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Keywords: Hypoxia responsive, case control
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Project description:The CH1 (TAZ) domain of the transcriptional coactivators p300 and CBP has been reported to interact with the transcription factor HIF-1alpha and this interaction is thought to be critical for HIF-1alpha target gene expression in response to hypoxia. To determine the requirement for the CH1 domain in hypoxia-responsive gene expression, primary mouse embryonic fibroblasts (MEFs) were generated from e14.5 C57B/6x129/Sv F2 embryos that were either wildtype or bore deletion mutations in the CH1 protein binding domains of both alleles of p300 and one allele of CBP (tri_CH1). Subconfluent MEFs were treated with 21% oxygen (normoxia) or 0.1% oxygen (hypoxia) with 5% carbon dioxide at 37 C in a humid chamber for 6hrs. At the start of treatment, medium was removed and replaced with medium (DMEM+10% FBS+pen-strep+ l-glu) that had been preequilibrated overnight in normoxia or hypoxia as appropriate. Immediately after treatment, cells were lysed in Trizol for RNA extraction. Keywords: genetic modification, dose response
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Project description:The catecholamine norepinephrine is required for fetal survival, but its essential function is unknown. When catecholamine-deficient [tyrosine hydroxylase (Th) null] mouse fetuses die at E13.5-E14.5, they resemble wild type fetuses exposed to hypoxia. They exhibit bradycardia (28% reduction in heart rate), thin ventricular myocardium (20% reduction in tissue), epicardial detachment, and death with vascular congestion, hemorrhage and edema. At E12.5, prior to the appearance of morphological deficits associated with Th deletion, catecholamine-deficient fetuses are preferentially killed by experimentally-induced hypoxia and have lower tissue pO2 than wild type siblings. Catecholamine-deficient fetuses also induced HIF-1 target genes to a greater extent than wild type siblings, supporting the notion that null fetuses experience greater hypoxia or have an enhanced response to hypoxia. Hypoxia induces a 13-fold increase in plasma norepinephrine levels, which would be expected to increase heart rate, thereby, improving oxygen delivery in wild type mice. Surprisingly, increasing maternal oxygen (FiO2 33% or 63%) prevents the effects of catecholamine-deficiency, restoring heart rate, myocardial mass and survival of Th null fetuses. We suggest that norepinephrine mediates fetal survival by maintaining oxygen homeostasis as vulnerability to constitutive hypoxia increases as fetal growth accelerates during normal development. Keywords: Comparative with respect to genotype and oxygen conditions The first aim was to compare gene expression of E12.5 mouse fetuses between wild type (Th+/+) versus tyrosine hydroxylase null (Th-/-) animals from normoxic dams. This resulted in 6 arrays. The second aim compared wild type and tyrosine hydroxylase null E12.5 fetuses from dam exposed to hypoxia (8% oxygen) for 6 hours prior to sacrifice at E12.5 of gestation. This resulted in 6 arrays. The third aim was to compare HIF-1 targets behind wt and null fetuses
2008-06-03 | E-GEOD-10341 | biostudies-arrayexpress
Project description:Neutrophils were isolated form peripheral blood of wildtype and Phd3 null mice, cultured for 4 hours in hypoxia (3% O2) and micro array analysis performed The aim of the present study is to identify the mechanism by which phd3 is required for the hypoxia mediated survival of neutrophils Murine peripheral blood neutrophils were isolated from wildtype and phd3 null mice, cultured for 4 hours in hypoxia (3% O2) and micro array analysis performed
2011-02-08 | E-GEOD-26023 | biostudies-arrayexpress
Project description:HIF-1a activates genes under hypoxia and was hypothesized to regulate bone regeneration. Surprisingly, HET HIF-1a fracture calluses are larger, stronger and stiffer than WT HIF-1a calluses due to decreased apoptosis. These data identify apoptosis inhibition as a means to enhance bone regeneration. Introduction: Bone regeneration subsequent to fracture involves the synergistic activation of multiple signaling pathways. Localized hypoxia following fracture activates hypoxia-inducible factor 1 alpha (HIF-1a) leading to increased expression of HIF-1 target genes. We therefore hypothesized that HIF-1a is a key regulator of bone regeneration Materials and Methods: Fixed femoral fractures were generated in mice with partial HIF-1a deficiency (HET HIF-1a) and wild type littermates (WT HIF-1a). Fracture calluses and intact contralateral femurs from post fracture day (PFD) 21 and 28 (N=5-10) were subjected to MicroCT evaluation and 4-point bending in order to assess morphometric and mechanical properties. Molecular analyses were carried out on PFD 7, 10 and 14 samples (N=3) to determine differential gene expression at both mRNA and protein levels. Finally, TUNEL staining was performed on PFD 14 samples (N=2) to elucidate differential apoptosis. Results: Surprisingly, fracture calluses from HET HIF-1a mice exhibit greater mineralization and are larger, stronger and stiffer. Microarray analyses focused on hypoxia-induced genes revealed differential expression (between genotypes) of several genes associated with the apoptotic pathway. Real-time PCR confirmed these results, demonstrating higher expression of pro-apoptotic PP2A and lower expression of anti-apoptotic BCL2 in WT HIF-1a calluses. Subsequent TUNEL staining demonstrates that WT HIF-1a calluses contain larger numbers of TUNEL positive chondrocytes and osteoblasts than HET HIF-1a calluses. Conclusions: We conclude that partial HIF-1a deficiency results in decreased chondrocytic and osteoblastic apoptosis; thereby allowing the development of larger, stiffer calluses and enhancing bone regeneration. Furthermore, apoptosis inhibition may be a promising target for developing new treatments to accelerate bone regeneration. Keywords: Bone, Fracture, Apoptosis, Hypoxia, Microarray
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