Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

BelAiba, Rachida S.; Bonello, Steve; Zähringer, Christian; Schmidt, Stefanie; Hess, John; Kietzmann, Thomas; Görlach, Agnes

doi:10.1091/mbc.e07-04-0391

Cited by 379 publications

(334 citation statements)

References 51 publications

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“…Thus, our results are in line with previous findings where Nab2 inhibited VEGF-induced tissue factor promoter activity (48). Recent studies have implicated cross-talk between NF-B and HIF-1␣ genes, where NF-B regulates HIF-1␣ promoter activity and mRNA expression in response to H 2 O 2 , short duration hypoxia, and TNF-␣ (20,21,50). Thus, the possibility of PlGF-mediated activation of HIF-1␣ through indirect stimulation of NF-B cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Patel¹,

Kalra

2010

Journal of Biological Chemistry

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Leukotrienes, the lipid inflammatory products derived from arachidonic acid, are involved in the pathogenesis of respiratory and cardiovascular diseases and reactive airway disease in sickle cell disease. Placenta growth factor (PlGF), elaborated from erythroid cells, increased the mRNA expression of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) in human pulmonary microvascular endothelial cells. PlGF-induced both promoter activity and mRNA expression of hypoxia-inducible factor-1␣ (HIF-1␣), which was abrogated by early growth response-1 (EGR-1) small interfering RNA. PlGF showed a temporal reciprocal relationship in the mRNA levels of EGR-1 and NAB2, the latter a repressor of Egr-1. Moreover, Nab2, but not mutant Nab2, significantly reduced promoter activity and mRNA expression of HIF-1␣ and also reduced expression of the HIF-1␣ target gene FLAP. Furthermore, overexpression of Egr-1 led to increased promoter activities for both HIF-1␣ and FLAP in the absence of PlGF. Additionally, the Egr-1-mediated induction of HIF-1␣ and FLAP promoters was reduced to basal levels by EGR-1 small interfering RNA. The binding of Egr-1 to HIF-1␣ promoter was corroborated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, which showed increased Egr-1 binding to the HIF-1␣ promoter in response to PlGF stimulation. These studies provide a novel mechanism for PlGF-mediated regulation of HIF-1␣ via Egr-1, which results in increased FLAP expression. This study provides a new therapeutic target, namely Egr-1, for attenuation of elevated leukotriene levels in patients with sickle cell disease and other inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Patel¹,

Kalra

2010

Journal of Biological Chemistry

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“…Crosstalk between the HIF and NF!B pathways has been demonstrated by a number of in vitro and in vivo studies showing that NF!B plays an important role in regulating basal and stimulated HIF-1# expression [7,[15][16][17][18]. NF!B can also regulate HIF-2# signalling through an interaction with the NF!B essential modulator (NEMO), which aids in the recruitment of transcriptional co-activators such as CREB binding protein (CBP) and p300, and increases HIF-2# transcriptional activity [19].…”

Section: Introductionmentioning

confidence: 99%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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The oxygen-sensitive transcription factor Hypoxia Inducible Factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor Nuclear factor kappa B (NF!B) during hypoxic inflammation. Here we describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus Gluc constructs under the control of either HIF or NF!B were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli respectively. We also investigated the interactions between HIF and NF!B activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NF!B. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NF!B to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NF!B transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a coordinated role for both HIF and NF!B in the expression of COX-2 in hypoxic inflammation.

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“…However, defining the relationship between NF-kB and HIF-1a has proven elusive. Using in vitro systems, it was reported that HIF-1a activates NF-kB 9 , that NF-kB controls HIF-1a transcription 10 and that HIF-1a activation may be concurrent with inhibition of NF-kB 11 . Here we show, with the use of mice lacking IKK-b in different cell types, that NF-kB is a critical transcriptional activator of HIF-1a and that basal NF-kB activity is required for HIF-1a protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals.…”

mentioning

confidence: 99%

NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α

Rius

Gumá

Schachtrup³

et al. 2008

Nature

1,334

1,015

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Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

Cited by 379 publications

References 51 publications

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

NFκB and HIF display synergistic behaviour during hypoxic inflammation

NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α

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