Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia‐inducible factor‐1

Wang, Dan; Wang, Lihong; Zhao, Yu; Lu, Yapeng; Zhu, Li

doi:10.1002/iub.363

Cited by 40 publications

(30 citation statements)

References 24 publications

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“…This is consistent with the observation that DMT1 is elevated in the basal ganglia of iron deficient rats and that Mn is selectively increased in the globus pallidus in iron deficient animals exposed to Mn [77,78]. In addition to regulation of the +IRE species of DMT1 by IRPs, the N-terminal isoforms of DMT1 are also independently regulated at the level of transcription by environmental conditions which manifest in various stress-related events and inflammatory processes within the cell [79–83]. Transcription of the 1B isoforms of the transporter is upregulated by both NF-κB, and NF-Y (CCAAT promoter) and indirectly by nitric oxide suppression of NF-κB activity.…”

Section: Mn Transportsupporting

confidence: 79%

Manganese Homeostasis and Transport

Roth

Ponzoni

Aschner

2012

Metal Ions in Life Sciences

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Section: Mn Transportsupporting

confidence: 79%

Manganese Homeostasis and Transport

Roth

Ponzoni

Aschner

2012

Metal Ions in Life Sciences

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“…Inflammation can cause cellular iron sequestration through IL-6 mediated upregulation of hepcidin (Ganz and Nemeth, 2009). Hypoxia can lead to increased iron uptake through HIF-mediated upregulation of DMT1, a cellular iron importer (Wang et al, 2010). Oxidative stress can upregulate TfR, another cellular iron importer (Fonseca et al, 2003).…”

Section: Retinal Disorders Resulting From Abnormal Retinal Iron Metabmentioning

confidence: 99%

Retinal iron homeostasis in health and disease

Song¹,

Dunaief²

2013

Front. Aging Neurosci.

102

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Iron is essential for life, but excess iron can be toxic. As a potent free radical creator, iron generates hydroxyl radicals leading to significant oxidative stress. Since iron is not excreted from the body, it accumulates with age in tissues, including the retina, predisposing to age-related oxidative insult. Both hereditary and acquired retinal diseases are associated with increased iron levels. For example, retinal degenerations have been found in hereditary iron overload disorders, like aceruloplasminemia, Friedreich's ataxia, and pantothenate kinase-associated neurodegeneration. Similarly, mice with targeted mutation of the iron exporter ceruloplasmin and its homolog hephaestin showed age-related retinal iron accumulation and retinal degeneration with features resembling human age-related macular degeneration (AMD). Post mortem AMD eyes have increased levels of iron in retina compared to age-matched healthy donors. Iron accumulation in AMD is likely to result, in part, from inflammation, hypoxia, and oxidative stress, all of which can cause iron dysregulation. Fortunately, it has been demonstrated by in vitro and in vivo studies that iron in the retinal pigment epithelium (RPE) and retina is chelatable. Iron chelation protects photoreceptors and retinal pigment epithelial cells (RPE) in a variety of mouse models. This has therapeutic potential for diminishing iron-induced oxidative damage to prevent or treat AMD.

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“…Luciferase assay for transcriptional activity of HRE-luciferase was performed as previously reported16. In brief, HCT116 cells were grown to 90% confluence, and then plasmid constructs were cotransfected with an internal control vector pRL-TK (Promega, Madiso, WI) (100:1 ratio) to the cells by Lipofectamine 2000 (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells

Shi

et al. 2016

Sci Rep

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Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1α protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1α. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1α regulation and suggested its therapeutic potential in colon tumors.

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Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia‐inducible factor‐1

Cited by 40 publications

References 24 publications

Manganese Homeostasis and Transport

Manganese Homeostasis and Transport

Retinal iron homeostasis in health and disease

Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells

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