Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2

Taleb, Zukaa al; Petry, Andreas; Franklin, Tabughang; Mennerich, Daniela; Görlach, Agnes; Dimova, Elitsa Y.; Kietzmann, Thomas

doi:10.1007/s00109-016-1439-7

Cited by 31 publications

(24 citation statements)

References 70 publications

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“…Furthermore, PI3K can upregulate the HIF-1 α protein translation [48]. Studies have been also showing that the induction of the Nrf2 pathway augments HIF-1 α signaling [49]. Consistent with these reports, our results found that PI3K specific inhibitor LY294002 significantly restored the sensitivity of MCF-7/ROS cells to ADM. More importantly, HIF-1 α and Nrf2 were manifested as the downstream targets of overactivated PI3K/Akt pathway, while they were both responsible for the overexpression of P-gp in MCF-7/ROS cells.…”

Section: Discussionsupporting

confidence: 90%

Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

Cen

Zhang

Liu

et al. 2016

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) play an important role in multidrug resistance (MDR). This study aimed to investigate the effects of long-term ROS alteration on MDR in MCF-7 cells and to explore its underlying mechanism. Our study showed both long-term treatments of H2O2 and glutathione (GSH) led to MDR with suppressed iROS levels in MCF-7 cells. Moreover, the MDR cells induced by 0.1 μM H2O2 treatment for 20 weeks (MCF-7/ROS cells) had a higher viability and proliferative ability than the control MCF-7 cells. MCF-7/ROS cells also showed higher activity or content of intracellular antioxidants like glutathione peroxidase (GPx), GSH, superoxide dismutase (SOD), and catalase (CAT). Importantly, MCF-7/ROS cells were characterized by overexpression of MDR-related protein 1 (MRP1) and P-glycoprotein (P-gp), as well as their regulators NF-E2-related factor 2 (Nrf2), hypoxia-inducible factor 1 (HIF-1α), and the activation of PI3K/Akt pathway in upstream. Moreover, several typical MDR mediators, including glutathione S-transferase-π (GST-π) and c-Myc and Protein Kinase Cα (PKCα), were also found to be upregulated in MCF-7/ROS cells. Collectively, our results suggest that ROS may be critical in the generation of MDR, which may provide new insights into understanding of mechanisms of MDR.

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Section: Discussionsupporting

confidence: 90%

Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

Cen

Zhang

Liu

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…We confirmed these genomic findings in multiple cell lines, we identified a functional NRF2 binding site (i.e., an antioxidant response element, or ARE) approximately 32 kilobases upstream of HIF1A , and we found that oncogenic NRF2 mutations are associated with high HIF1A expression in multiple cancer types. These findings are consistent with recent work suggesting NRF2 plays a role in HIF1A expression [31] , [32] , and our work lends further support to a model in which NRF2 is a direct regulator of HIF1A transcription.…”

Section: Introductionsupporting

confidence: 93%

“…Although much research effort has focused on the post-translational regulation of HIF1α levels, largely because the rapid increase in HIF1α protein stability is central to the adaptive response to hypoxia because [47] , [48] , several groups have recognized that regulation of HIF1α expression is also important [45] , [49] , [50] , [51] , [52] . And, importantly, HIF1A expression has been linked to ROS in multiple settings: HIF1A mRNA is upregulated by ROS-inducing mutations in mouse lung carcinoma cells, by multiple sources of ROS in pulmonary artery smooth muscle cells, by chemotherapeutic-induced ROS, and by the ROS-inducer arsenite [32] , [45] , [53] , [54] . Overall, in combination with this previously published work, these results demonstrate that ROS can activate HIF1A expression in multiple cellular contexts.…”

Section: Resultsmentioning

confidence: 99%

Identification of a functional antioxidant response element at the HIF1A locus

et al. 2018

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Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or other physiological signals, or to respond to oxidative stress. However, ROS signaling is complex, so regulatory interactions between various ROS-responsive transcription factors are still being mapped out. Here we show that the transcription factor NRF2, a key regulator of the adaptive response to oxidative stress, directly regulates expression of HIF1A, which encodes HIF1α, a key transcriptional regulator of the adaptive response to hypoxia. We used an integrative genomics approach to identify HIF1A as a ROS-responsive transcript and we found an NRF2-bound antioxidant response element (ARE) approximately 30 kilobases upstream of HIF1A. This ARE sequence is deeply conserved, and we verified that it is directly bound and activated by NRF2. In addition, we found that HIF1A is upregulated in breast and bladder tumors with high NRF2 activity. Taken together, our results demonstrate that NRF2 targets a functional ARE at the HIF1A locus, and reveal a direct regulatory connection between two important oxygen responsive transcription factors.

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“…Another redox regulated transcription factor which regulates the HIF system is Nrf2 (Nfe2l2; nuclear factor (erythroid-derived 2)-like 2) [111]. Nrf2 is known to contribute to intermediary and xenobiotic metabolism, bile production, as well as liver regeneration, and carcinogenesis [112], [113], [114], [115], [116], [117], [118].…”

Section: Hif Phds Redox and Zonationmentioning

confidence: 99%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2

Cited by 31 publications

References 70 publications

Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

Identification of a functional antioxidant response element at the HIF1A locus

Metabolic zonation of the liver: The oxygen gradient revisited

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