Induction of Hypoxia-Inducible-Factor 1 by Nitric Oxide Is Mediated via the PI 3K Pathway

Sandau, Katrin; Faus, Hortensia; Brüne, Bernhard

doi:10.1006/bbrc.2000.3789

Cited by 121 publications

(92 citation statements)

References 22 publications

(16 reference statements)

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“…NO can promote binding of HIF1 to HREs in HIF1 target genes by binding to an adjacent HIF1 ancillary sequence (HAs) and hence acting as a transcriptional co-activator 40 . It has also been reported that NO can upregulate the rate of HIF1α synthesis by activating the phosphatidylinositol 3-kinase (PI3K)-mAPK (mitogen-activated protein kinase) pathway 41,42 .…”

Section: Free Radical Regulation Of Hif1 Under Aerobic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Free Radical Regulation Of Hif1 Under Aerobic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Stimulation of LLC-PK 1 cells with GSNO led to Akt activation/ phosphorylation in close correlation to HIF-1␣ accumulation as inhibition of the PI3K with Ly 294002 suppressed Akt phosphorylation and HIF-1␣ stabilization (16). However, there is little or no information on the role on the PI3K/Akt pathway in the response of HIF-1␣ to TNF-␣, DFX, or PAO.…”

Section: Hif-1␣ Accumulation and The Interference By The Redox Cy-mentioning

confidence: 99%

“…This pathway is negatively regulated by PTEN (phosphatase and tensin homologue deleted in chromosome ten) and loss of function correlated with tumor angiogenesis. For the signaling molecule NO, we noticed that the general kinase inhibitor genistein and, more specifically, the PI3K inhibitors wortmannin or Ly 294002 blocked HIF-1␣ accumulation, whereas mitogen-activated protein kinases were not involved (16).…”

mentioning

confidence: 99%

Regulation of the Hypoxia-inducible Factor 1α by the Inflammatory Mediators Nitric Oxide and Tumor Necrosis Factor-α in Contrast to Desferroxamine and Phenylarsine Oxide

Sandau¹,

Zhou²,

Kietzmann³

et al. 2001

Journal of Biological Chemistry

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205

170

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Hypoxic/ischemic conditions provoke activation of the hypoxia-inducible factor-1 (HIF-1), which functions as a transcription factor. HIF-1 is composed of the HIF-1␣ and -␤ subunits, and stability regulation occurs via accumulation/degradation of HIF-1␣ with the notion that a prolyl hydroxylase accounts for changes in protein level. In addition, there is evidence that HIF-1 is up-regulated by diverse agonists during normoxia. We investigated the impact of inflammatory mediators nitric oxide (NO) and tumor necrosis factor-␣ (TNF-␣) on HIF-1␣ regulation. For comparison, LLC-PK 1 cells were exposed to hypoxia, stimulated with desferroxamine (DFX, known to mimic hypoxia), and the thiol-cross- The transcription factor hypoxia-inducible factor-1 (HIF-1) 1 is a heterodimer composed of the helix-loop-helix/Per-Arnt-Sim protein HIF-1␣ and the aryl hydrocarbon nuclear translocator, also known as HIF-1␤ (1-3). An active HIF-1 complex accumulates in the nucleus; binds to a specific DNA sequence, the HIF-1 binding site within the hypoxia response element (HRE); and enhances transcription of hypoxia-inducible genes, such as erythropoietin or vascular endothelial growth factor. The availability of HIF-1 is mainly determined by the presence/absence of HIF-1␣ (4, 5). In many cell types, both HIF-1␣ and HIF-1␤ appear to be constitutively expressed at the mRNA level, whereas, on protein level, HIF-1␣ is degraded under normoxic conditions, which contrasts with permanently expressed HIF-1␤. Studies in von Hippel-Lindau-defective renal cell carcinomas indicated that the von Hippel-Lindau protein fulfills a critical function in HIF-1␣ degradation, thus accounting for the extremely short protein half-life (6). However, accumulation of HIF-1␣ that promotes active HIF-1 complex formation by hypoxia is not fully understood. Oxygen species such as superoxide (O 2 Ϫ ) or hydrogen peroxide (H 2 O 2 ) have been proposed to limit HIF-1␣ stability (7). A postulated source for these species is a NAD(P)H-metabolizing membrane-bound type b cytochrome quite similar to the respiratory burst oxidase in phagocytes. In addition to these intracellular redox changes, phosphorylation cascades such as mitogen-activated protein kinases have been ascribed to stabilize HIF-1␣, but precise signaling mechanisms and their cross-talk have not been not fully defined (8 -10).Activation of HIF-1 as an adaptive response was first described for conditions of decreased oxygen pressure. Therefore, most mechanistic and functional studies on HIF-1 regulation refer to hypoxic conditions. More recent evidence suggests that HIF-1 can be activated by growth factors, cytokines, hormones, or nitric oxide (NO) as well with very little information on signal transduction pathways being involved (11-15). Zhong et al. (11) verified a role of phosphatidylinositol 3-kinase (PI3K), Akt phosphorylation, and FRAP activation for HIF-1␣ induction in response to hypoxia and epithelial growth factor treatment. This pathway is negatively regulated by PTEN (phosphatase and tensin homologue de...

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“…Evidence is provide that changes in the levels of reactive oxygen species (ROS) may play a role in HIF-1␣ protein induction and HIF-1 transactivation (14, 30 -32). Increased levels of ROS are suggested to mediate PI3K activation under hypoxia as well as under normoxia (32,33). The levels of ROS may also directly or indirectly influence the redox status of cysteine residues in the transactivation domains of HIF-1␣, which can affect interactions with transcriptional coactivators (21,22).…”

Section: Vasular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite

Duyndam

Hulscher

Wall

et al. 2003

Journal of Biological Chemistry

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Recently we have demonstrated that sodium arsenite induces the expression of hypoxia-inducible factor 1␣ (HIF-1␣) protein and vascular endothelial growth factor (VEGF) in OVCAR-3 human ovarian cancer cells. We now show that arsenic trioxide, an experimental anticancer drug, exerts the same effects. The involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways in the effects of sodium arsenite was investigated. By using kinase inhibitors in OVCAR-3 cells, both effects of sodium arsenite were found to be independent of phosphatidylinositol 3-kinase and p44/p42 MAPKS but were attenuated by inhibition of p38 MAPK. A role for p38 in the regulation of HIF-1␣ and VEGF expression was supported further by analysis of activation kinetics. Experiments in mouse fibroblast cell lines, lacking expression of c-Jun N-terminal kinases 1 and 2, suggested that these kinases are not required for induction of HIF-1␣ protein and VEGF mRNA. Unexpectedly, sodium arsenite did not activate a HIF-1-dependent reporter gene in OVCAR-3 cells, indicating that functional HIF-1 was not induced. In agreement with this hypothesis, up-regulation of VEGF mRNA was not reduced in HIF-1␣ ؊/؊ mouse fibroblast cell lines. Altogether, these data suggest that not HIF-1, but rather p38, mediates induction of VEGF mRNA expression by sodium arsenite.

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Induction of Hypoxia-Inducible-Factor 1 by Nitric Oxide Is Mediated via the PI 3K Pathway

Cited by 121 publications

References 22 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Regulation of the Hypoxia-inducible Factor 1α by the Inflammatory Mediators Nitric Oxide and Tumor Necrosis Factor-α in Contrast to Desferroxamine and Phenylarsine Oxide

Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite

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