scholarly journals The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1, Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia

2002 ◽  
Vol 22 (6) ◽  
pp. 1734-1741 ◽  
Author(s):  
Konstantin Salnikow ◽  
Thomas Kluz ◽  
Max Costa ◽  
David Piquemal ◽  
Zoya N. Demidenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kinase Inhibitor ◽  
Regulation Of Gene Expression ◽  
Hypoxia Inducible Factor ◽  
Dominant Negative ◽  
Activator Protein 1 ◽  
Hypoxia Inducible Factor 1 ◽  
Intracellular Ca ◽  
Inducible Genes ◽  
Endothelial Growth Factor

ABSTRACT Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca2+) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca2+ neither induced the HIF-1α protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca2+ induced NDRG-1/Cap43 mRNA in HIF-1α-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca2+ ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca2+-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca2+-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca2+ activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia.

scholarly journals Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.

1996 ◽  
Vol 16 (9) ◽  
pp. 4604-4613 ◽  
Author(s):  
J A Forsythe ◽  
B H Jiang ◽  
N V Iyer ◽  
F Agani ◽  
S W Leung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Reporter Gene ◽  
Hypoxia Inducible Factor ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Vascular Endothelial ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.

A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses

2001 ◽  
Vol 114 (22) ◽  
pp. 4051-4061
Author(s):  
Yang-Sook Chun ◽  
Eunjoo Choi ◽  
Eun-Jin Yeo ◽  
Jong Ho Lee ◽  
Myung-Suk Kim ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Consensus Sequence ◽  
Hypoxia Inducible Factor ◽  
Zinc Ion ◽  
Dominant Negative ◽  
Hypoxia Inducible Factor 1 ◽  
Aryl Hydrocarbon ◽  
Hypoxic Conditions ◽  
Alpha Variant ◽  
Inducible Genes

The expressions of hypoxia-inducible genes are upregulated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimer of HIF-1α and HIF-1β/ARNT (aryl hydrocarbon receptor nuclear transporter). Under hypoxic conditions, HIF-1α becomes stabilized and both HIF-1α and ARNT are translocated into the nucleus and codimerized, binding to the HIF-1 consensus sequence and transactivating hypoxia-inducible genes. Other than hypoxia, cobalt and nickel, which can substitute for iron in the ferroprotein, induce the stabilization of HIF-1α and the activation of HIF-1. We found previously that, although zinc, another example of a metal substitute for iron, stabilized HIF-1α, it suppressed the formation of HIF-1 by blocking the nuclear translocation of ARNT. Here, we identify a new spliced variant of human HIF-1α that is induced by zinc. The isoform lacks the 12th exon, which produced a frame-shift and gave a shorter form of HIF-1α (557 amino acids), designated HIF-1αZ (HIF-1α induced by Zn). This moiety was found to inhibit HIF-1 activity and reduce mRNA expressions of the hypoxia-inducible genes. It blocked the nuclear translocation of ARNT but not that of endogenous HIF-1α, and was associated with ARNT in the cytosol. These results suggest that HIF-1αZ functions as a dominant-negative isoform of HIF-1 by sequestering ARNT in the cytosol. In addition, the generation of HIF-1αZ seems to be responsible for the inhibitory effects of the zinc ion on HIF-1-mediated hypoxic responses, because the expressed HIF-1αZ behaved in the same manner as zinc in terms of inhibited HIF-1 activity and ARNT translocation.

Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression

Metallomics ◽  
2014 ◽  
Vol 6 (10) ◽  
pp. 1889-1893 ◽  
Author(s):  
Zhen Zhang ◽  
Liying Qiu ◽  
Chen Lin ◽  
Hong Yang ◽  
Haiying Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cobalt Chloride ◽  
Regulation Of Gene Expression ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

HIF-1 mediated expression of BNIP3 by cobalt chloride is Cu-dependent, but the expression of IGF-2 is Cu-independent.

Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1)

2005 ◽  
Vol 206 (3) ◽  
pp. 291-304 ◽  
Author(s):  
AE Greijer ◽  
P van der Groep ◽  
D Kemming ◽  
A Shvarts ◽  
GL Semenza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

scholarly journals Follicle-stimulating Hormone Activation of Hypoxia-inducible Factor-1 by the Phosphatidylinositol 3-Kinase/AKT/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) Pathway Is Necessary for Induction of Select Protein Markers of Follicular Differentiation

2004 ◽  
Vol 279 (19) ◽  
pp. 19431-19440 ◽  
Author(s):  
Hena Alam ◽  
Evelyn T. Maizels ◽  
Youngkyu Park ◽  
Shail Ghaey ◽  
Zachary J. Feiger ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Follicle Stimulating Hormone ◽  
Hypoxia Inducible Factor ◽  
Mtor Pathway ◽  
Dominant Negative ◽  
Luteinizing Hormone Receptor ◽  
Regulatory Subunit ◽  
Differentiation Markers ◽  
Hypoxia Inducible Factor 1 ◽  
Stimulating Hormone

We sought to elucidate the role of AKT in follicle-stimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Rashomologenriched inbrain) and subsequent mTOR (mammaliantargetofrapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-α, microtubule-associated protein 2D, and the PKA type IIβ regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSH-stimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferaseinhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated up-regulation of reporter activities for LHR, inhibin-α, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1α interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.

scholarly journals Hydrogen sulfide promotes angiogenesis by downregulating miR-640 via the VEGFR2/mTOR pathway

2016 ◽  
Vol 310 (4) ◽  
pp. C305-C317 ◽  
Author(s):  
Yu Zhou ◽  
Xing-Hui Li ◽  
Cai-Cai Zhang ◽  
Ming-Jie Wang ◽  
Wen-Long Xue ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Vascular Endothelial Cells ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Mtor Pathway ◽  
Dominant Negative ◽  
Vascular Endothelial ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor

We previously found hydrogen sulfide (H2S) to be a new proangiogenic factor. However, the mechanisms underlying the cardiovascular effect of this small gas molecule remain largely unknown. The aim of the present study was to identify the essential microRNAs (miRNAs) involved in the transduction of H2S signals in vascular endothelial cells (ECs). The expression of miR-640 and its signaling elements, vascular endothelial growth factor receptor 2 (VEGFR2), hypoxia inducible factor 1-α (HIF1A), and mammalian target of rapamycin (mTOR), was measured using quantitative PCR and Western blotting. Overexpression and inhibition of miR-640 were performed to clarify their roles in mediating the effect of H2S. In addition, knockdown of VEGFR2, HIF1A, and mTOR was performed using siRNAs, dominant negative mutants, or inhibitors to examine their roles in the transduction of the H2S signals. miR-640 levels decreased in vascular ECs that were treated with H2S, whereas overexpression of miR-640 blunted the proangiogenic effect of H2S. Knockdown of either VEGFR2 or mTOR blunted the downregulation of miR-640 and the proangiogenic effect induced by H2S. In addition, miR-640 bound to the 3′-UTR of HIF1A mRNA and then inhibited the expression of HIF1A. The inhibition could be recovered by treating cells with H2S. Thus we concluded that miR-640 plays a pivotal role in mediating the proangiogenic effect of H2S; H2S acts through downregulation of the expression of miR-640 and increasing the levels of HIF1A through the VEGFR2-mTOR pathway.

scholarly journals Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 582
Author(s):  
Yoko Ono ◽  
Hidemasa Bono
Keyword(s):  
Meta Analysis ◽  
Hypoxia Inducible Factor ◽  
Data Driven ◽  
Similarity Coefficients ◽  
Hypoxia Inducible Factor 1 ◽  
Response System ◽  
Inducible Genes ◽  
The Relationship ◽  
G Protein Coupled ◽  
Sufficient Oxygen

Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.

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