scholarly journals Loss of the B irt– H ogg– D ubé gene product folliculin induces longevity in a hypoxia‐inducible factor–dependent manner

Aging Cell ◽  
2013 ◽  
Vol 12 (4) ◽  
pp. 593-603 ◽  
Author(s):  
Hakam Gharbi ◽  
Francesca Fabretti ◽  
Puneet Bharill ◽  
Markus M. Rinschen ◽  
Sibylle Brinkkötter ◽  
...  
Keyword(s):  
Gene Product ◽  
Hypoxia Inducible Factor ◽  
Dependent Manner

scholarly journals Embryonal Carcinoma P19 Cells Produce Erythropoietin Constitutively But Express Lactate Dehydrogenase in an Oxygen-Dependent Manner

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1185-1195 ◽  
Author(s):  
Taiho Kambe ◽  
Junko Tada ◽  
Mariko Chikuma ◽  
Seiji Masuda ◽  
Masaya Nagao ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Binding Site ◽  
Embryonal Carcinoma ◽  
Hypoxia Inducible Factor ◽  
Embryonic Stem ◽  
Gene Promoter ◽  
Dependent Manner ◽  
P19 Cells ◽  
Independent Manner ◽  
Hep3b Cells

Abstract Embryonic stem cells and embryonal carcinoma P19 cells produce erythropoietin (Epo) in an oxygen-independent manner, although lactate dehydrogenase A (LDHA) is hypoxia-inducible. To explore this paradox, we studied the operation of cis-acting sequences from these genes in P19 and Hep3B cells. The Epo gene promoter and 3′ enhancer from P19 cells conveyed hypoxia-inducible responses in Hep3B cells but not in P19 cells. Together with DNA sequencing and the normal transcription start site of P19 Epo gene, this excluded the possibility that the noninducibility of Epo gene in P19 cells was due to mutation in these sequences or unusual initiation of transcription. In contrast, reporter constructs containing LDHA enhancer and promoter were hypoxia inducible in P19 and Hep3B cells, and mutation of a hypoxia- inducible factor 1 (HIF-1) binding site abolished the hypoxic inducibility in both cells, indicating that HIF-1 activation operates normally in P19 cells. Neither forced expression of hepatocyte nuclear factor 4 in P19 cells nor deletion of its binding site from the Epo enhancer was effective in restoring Epo enhancer function. P19 cells may lack an unidentified regulator(s) required for interaction of the Epo enhancer with Epo and LDHA promoters.

Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells

2021 ◽  
Author(s):  
Gang Xue ◽  
Ruifang Gao ◽  
Zhuanzhuan Liu ◽  
Na Xu ◽  
Yong Cao ◽  
...  
Keyword(s):  
Vitamin D ◽  
Animal Models ◽  
Epithelial Cells ◽  
Dextran Sulfate ◽  
Hypoxia Inducible Factor ◽  
Dependent Manner ◽  
Trinitrobenzenesulfonic Acid ◽  
Colonic Epithelial Cells ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD) and hypoxia-inducible factor 1α (HIF-1α) activation is demonstrated to be closely associated with chemical-induced colitis. However, the association between vitamin D/VDR signaling and HIF-1α on IBD development remains a mystery. Here, we showed that HIF-1α expression was largely increased in the colonic epithelial cells of diseased tissues from ulcerative colitis (UC) patients. Consistently, HIF-1α activation was also improved in colonic epithelial cells upon TNFα treatment in a NF-κB pathway-dependent manner. HIF-1α inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF-1α overexpression in colonic epithelial cells via regulating NF-κB pathway, resulting in the inhibition of IFNγ and IL-1β overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1α expression in colonic epithelial cells.

scholarly journals The Hypoxia-Inducible Factor 1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia

2009 ◽  
Vol 29 (21) ◽  
pp. 5828-5842 ◽  
Author(s):  
Lluis Martorell ◽  
Maurizio Gentile ◽  
Jordi Rius ◽  
Cristina Rodríguez ◽  
Javier Crespo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Orphan Receptor ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Hypoxia Inducible Factor 1 ◽  
Apoptosis Protein

ABSTRACT Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1α protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca2+ was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.

scholarly journals HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells

2017 ◽  
Vol 313 (4) ◽  
pp. F906-F913 ◽  
Author(s):  
Wei Zhang ◽  
Xiangjun Zhou ◽  
Qisheng Yao ◽  
Yutao Liu ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Cell Injury ◽  
Hypoxia Inducible Factor ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes.

scholarly journals HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

2001 ◽  
Vol 21 (12) ◽  
pp. 3995-4004 ◽  
Author(s):  
Erik Laughner ◽  
Panthea Taghavi ◽  
Kelly Chiles ◽  
Patrick C. Mahon ◽  
Gregg L. Semenza
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cancer Cells ◽  
Half Life ◽  
Hypoxia Inducible Factor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Her2 Signaling ◽  
Endothelial Growth Factor

ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1α and HIF-1β subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1α expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1α for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1α. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1α expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1α protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1α but instead stimulates HIF-1α synthesis in a rapamycin-dependent manner. The 5′-untranslated region of HIF-1α mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1α expression.

Abstract 934: Contributory Role of VEGF Overexpression in Endothelin-1-induced Cardiomyocyte Hypertrophy: Involvement of Hyopoxia Inducible Factor

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nobutake Shimojo ◽  
Subrina Jesmin ◽  
Yuichi Hattori ◽  
Seiji Maeda ◽  
Takashi Miyauchi ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hypoxia Inducible Factor ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effect of ET-1 on expression of VEGF and its receptors in cardiomyocytes is unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principle receptors, fetal liver kinase (flk)-1 and fms-like tyrosine kinase (flt)-1, in a concentration-dependent manner (10 −12 -10 −6 M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area (2.0-fold compared to control) and 14 C-leucine uptake (1.8 fold) by cardiomyocytes. And this ET-1 mediated upregulation of VEGF in cardiomyocytes was associated with the induction of hypoxia inducible factor (HIF)-1β and HIF-2α, not HIF-1α. Treatment with TA-0201 (10 −6 M), an ET A selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5–10 μg/ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. Both TA-0201 and VEGF neutralizing peptides also significantly prevented the increase of phosphorylated KDR, which implies the activation of VEGF system in ET-1 induced hypertrophied cardiomyocyte. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ET A receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.

scholarly journals Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

2020 ◽  
Vol 13 (9) ◽  
pp. 208
Author(s):  
Min-Hee Kim ◽  
Tae Hyeong Lee ◽  
Jin Soo Lee ◽  
Dong-Jun Lim ◽  
Peter Chang-Whan Lee
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Soft Agar ◽  
Dependent Manner ◽  
Thyroid Cancer Cell Lines ◽  
Dose Dependent

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

The Warburg effect promoted the activation of the NLRP3 inflammasome induced by Ni-refining fumes in BEAS-2B cells

2020 ◽  
Vol 36 (8) ◽  
pp. 580-590
Author(s):  
Rui Wang ◽  
Sheng-Yuan Wang ◽  
Yue Wang ◽  
Rui Xin ◽  
Bing Xia ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Warburg Effect ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Control Group ◽  
Dependent Manner ◽  
Chain Reactions ◽  
Protein Levels ◽  
Polymerase Chain Reactions ◽  
The Warburg Effect

Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.

Evitar (l-Alanyl-l-Glutamine) Regulates Key Signaling Molecules in the Pathogenesis of Postoperative Tissue Fibrosis

2018 ◽  
Vol 26 (6) ◽  
pp. 724-733 ◽  
Author(s):  
Lynne M. Robertson ◽  
Nicole M. Fletcher ◽  
Michael P. Diamond ◽  
Ghassan M. Saed
Keyword(s):  
Cellular Response ◽  
Type I Collagen ◽  
Primary Cultures ◽  
Hypoxia Inducible Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Dependent Manner ◽  
Tissue Fibrosis ◽  
Hypoxia Inducible Factor 1Α ◽  
Episodic Hypoxia

Aims:Hypoxia and the resulting oxidative stress play a major role in postoperative tissue fibrosis. The objective of this study was to determine the effect of l-alanyl-l-glutamine (Ala-Gln) on key markers of postoperative tissue fibrosis: hypoxia-inducible factor (HIF) 1α and type I collagen.Methods:Primary cultures of human normal peritoneal fibroblasts (NPF) established from normal peritoneal tissue were treated with increasing doses of Ala-Gln (0, 1, 2, or 10 mM) with hypoxia ([2% O2] 0-48 hours; continuous hypoxia) or after hypoxia (0.5, 1, 2, 4 hours) and restoration of normoxia (episodic hypoxia) with immediate treatment with Ala-Gln. Hypoxia-inducible factor 1α and type 1 collagen levels were determined by enzyme-linked immunosorbent assay. Data were analyzed with 1-way analysis of variance followed by Tukey tests with Bonferroni correction.Results:Hypoxia-inducible factor 1α and type I collagen levels increased in untreated controls by 3- to 4-fold in response to continuous and episodic hypoxia in human NPF. Under continuous hypoxia, HIF-1α and type I collagen levels were suppressed by Ala-Gln in a dose-dependent manner. l-alanyl-l-glutamine treatment after episodic hypoxia also suppressed HIF-1α and type I collagen levels for up to 24 hours for all doses and up to 48 hours at the highest dose, regardless of exposure time to hypoxia.Conclusions:l-alanyl-l-glutamine significantly suppressed hypoxia-induced levels of key tissue fibrosis (adhesion) phenotype markers under conditions of continuous as well as episodic hypoxia in vitro. This effect of glutamine on molecular events involved in the cellular response to insult or injury suggests potential therapeutic value for glutamine in the prevention of postoperative tissue fibrosis.

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