Rescue of HIF1A protein level by E3-ligase KO
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228311 | GEO | 2023/03/27
REPOSITORIES: GEO
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Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas. Pre-treatment biopsies were collected from 16 human sarcoma. The gene expression analysis was performed using Illumina platform.
2011-08-29 | E-GEOD-31715 | biostudies-arrayexpress
Project description:Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O2 availability. HIF-1 controls physiological processes that are dysregulated in cancer and heart disease, including angiogenesis, energy metabolism, and immunity. These disease processes are also characterized by increased activation of adenosine and β-adrenergic receptors, which triggers the synthesis of cyclic adenosine monophosphate (cAMP), the allosteric regulator of cAMP-dependent protein kinase A (PKA). We performed a proteomic screen in cardiomyocytes and identified PKA as a HIF-1α-interacting protein. PKA interacted with HIF-1α and phosphorylated Thr63 and Ser692 in vitro, coimmunoprecipitated with HIF-1α from cell lysates, and enhanced HIF transcriptional activity and target gene expression in human HeLa cells and rat cardiomyocytes. PKA inhibited the proteasomal degradation of HIF-1α in an O2-independent manner that required phosphorylation of Thr63 and Ser692 and was not affected by mutation of Pro402 and Pro564. PKA also stimulated the binding of the coactivator p300 to HIF- 1α to enhance its transcriptional activity and this effect was lost upon mutation of Asn803. These data establish a potential link between stimuli that increase cAMP concentrations and HIF-1α-dependent changes in gene expression, which contribute to the pathophysiology of cancer and heart disease.
2016-06-07 | PXD003795 | Pride
Project description:Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O2 availability. HIF-1 target genes play a central role in mediating physiological processes that are dysregulated in cancer and heart disease, including angiogenesis, energy metabolism, and immunity. These disease processes are also characterized by increased activation of adenosine and β-adrenergic receptors, which triggers the synthesis of cyclic adenosine monophosphate (cAMP), the allosteric regulator of cAMP-dependent protein kinase A (PKA). We performed a proteomic screen in cardiomyocytes and identified PKA as a HIF-1α-interacting protein. PKA interacted with HIF-1α and phosphorylated Thr63 and Ser692 in vitro, co-immunoprecipitated with HIF-1α from cell lysates, and enhanced HIF transcriptional activity and target gene expression in human HeLa cells and rat cardiomyocytes. PKA inhibited the proteasomal degradation of HIF-1α in an O2-independent manner that required phosphorylation of Thr63 and Ser692 and was not affected by mutation of Pro402 and Pro564. PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and this effect was lost upon mutation of Asn803. These data establish a potential link between stimuli that increase cAMP concentrations and HIF-1α-dependent changes in gene expression, which contribute to the pathophysiology of cancer and heart disease.
2016-06-06 | PXD003792 | Pride
Project description:Chronic hypoxia induces pulmonary vascular remodeling and pulmonary hypertension (PH). While it is established that transcription factors, hypoxia-inducible factors (HIF-1α/HIF-2α) activate gene programs that drive hypoxia-induced PH, the mechanism of HIF-1/2 activation is less clear. Here, we report that carboxylterminus of Hsp70-interacting protein (CHIP or Stub1) modulates HIF-1α and HIF-2α transcription rather than reducing their stability. Knocking-down Stub1 reduced hypoxic activation of HIF-1α mRNA, protein, and activity while enhancing hypoxic induction of HIF-2α mRNA, protein, and target genes in pulmonary vascular cells. Mechanistically, CBP/p300-mediated acetylation of lysine (K287) inactivates the ubiquitin ligase activity of Stub1 and triggers its translocation from the cytoplasm into the nucleus. There, it recognizes the HIF promoter and hypoxia response elements (HREs) in target genes. Expression of Stub1-K287Q mutant (mimicking acetylation) enhanced hypoxia-induced HIF-1α expression, while acetyl-deficient Stub1-K287R mutant had the opposite effect on HIF-α but enhanced hypoxia-induced HIF-2α transcriptional activity. Endothelial-Stub1 transgenic mice tolerated chronic hypoxia better, had less pulmonary vascular remodeling, reduced pulmonary vascular resistance, and greater cardioprotection. Thus, Stub1 nuclear translocation enhances hypoxic induction of HIF-1α activity while suppressing deleterious effects of HIF-2α. These observations indicate that nuclear-Stub1 synergizes with HIF-1α to promote transcriptional responses and antagonizes HIF2α-driven PH in chronic hypoxia.
2023-04-01 | GSE221264 | GEO
Project description:Alternative RNA splicing analysis in Hep3B cell cultured under 21% (N1,3,5) or 1.2% (H2,4,6) oxygen Hypoxia is a common characteristic of many solid tumors. The hypoxic microenvironment stabilizes hypoxia-inducible transcription factor 1? (HIF1?) and 2? (HIF2?) to activate gene transcription, which promotes tumor cell survival. 95% of human genes are alternatively spliced, producing RNA isoforms that code functionally distinct proteins. Thus, effective hypoxia response requires increased HIF target gene transcription as well as proper RNA splicing of these HIF target genes. However, it is unclear if and how hypoxia regulates RNA splicing of HIF target genes. This study determined the effects of hypoxia on alternative splicing (AS) of HIF and non-HIF target genes in Hep3B cells and characterized the role of HIF in regulating AS of HIF induced genes. The results indicated that hypoxia generally promotes exon inclusion for hypoxia-induced, but reduces exon inclusion for hypoxia reduced genes. Mechanistically, HIF activity, but not hypoxia per se is found to be necessary and sufficient to increase exon inclusion of several HIF target genes including pyruvate dehydrogenase kinase 1 (PDK1). PDK1 splicing reporters confirmed that transcriptional activation by HIF is sufficient to increase exon inclusion of PDK1 splicing reporter. In contrast, transcriptional activation of the PDK1 minigene by other transcription factor in the absence of endogenous HIF target gene activation fails to alter PDK1 RNA splicing, demonstrating a novel role of HIF target gene(s) in regulating RNA splicing of HIF target genes. Implications:This study demonstrates a novel function of HIF in regulating RNA splicing of HIF target genes. We analyzed total RNA from Hep3B cells cultured under 21% (N1,3,5) or 1.2% (H2,4,6) oxygen using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Altanalyze software version 2.0.7. Techinical replicates were performed for Nx and Hx treated Hep3B cells
2014-05-14 | E-GEOD-57613 | biostudies-arrayexpress
Project description:Uterine contraction, crucial for successful labor, has been proved to be enchanced by hypoxia, which underlying mechanisms are yet to be elucidated. We found blockade of HIF-1a caused contractility decrease in myometrium and myocytes in hypoxic models. ChIP-seq revealed that HIF-1α directly bound to gemone of 2 typical contraction-associated proteins, the promoter of GJA1 and intron of OXTR. Blockade of GJA1 led to significant decrease of myometrial contractions under hypoxic tissue model, whereas atosiban did not influence the contractility. The conducted research suggests that HIF-1α is required for the augmentation of myometrial contractility via regulating GJA1 under hypoxia.
2022-08-01 | GSE197160 | GEO
Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas.
2011-08-30 | GSE31715 | GEO
Project description:NAA10 is the major human N-terminal acetyltransferase (NAT). The KAT activity of NAA10 towards hypoxia-inducible factor 1α (HIF-1α) was recently reported to depend on the hydroxylation at Trp38 of NAA10 by factor inhibiting HIF-1α (FIH). As a consequence, Trp38 hydroxylation status was proposed to act as a general NAA10-switch between its NAT and KAT state. We attempted to quantify the degree of hydroxylation of NAA10. We could not detect any hydroxylation of Trp38 of NAA10 in several human cell lines.
2022-02-16 | PXD023655 | Pride
Project description:Injured peripheral neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such programs remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the pre-conditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knockout in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction reinnervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.
2016-01-21 | GSE73415 | GEO
Project description:Hypoxia inducible factor-1 (HIF-1) is a central transcriptional regulator of genes associated with adaptive responses to hypoxia. NPM1 is a histone chaperone found to associate with HIF-1α in a phosphorylation dependent manner and increase its activty. The aim of this study was to find if HIF-1α and NPM1 regualate gene expression under hypoxia. Transcriptome analysis using Quant-RNA-seq after HIF-1α or NPM1 silencing under hypoxia reveals a significant number of genes, the hypoxic expression of which depends on both proteins.
2021-12-15 | GSE158890 | GEO