Hypoxia induces changes in expression of isoforms of the divalent metal transporter (DMT1) in rat pheochromocytoma (PC12) cells

Lis, Agnieszka; Paradkar, Prasad N.; Singleton, Steve; Kuo, Hsien-Chang; Garrick, Michael D.; Roth, Jerome A.

doi:10.1016/j.bcp.2005.03.023

Cited by 44 publications

(44 citation statements)

References 33 publications

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“…After transient hypoxia, only the weakly expressed 1A isoform was induced, whereas the 1B isoform was not and the expression of both 3 0 -variants, CIRE and KIRE respectively, was only slightly increased. These findings are in agreement with those reported for PC12 cells (Lis et al 2005) and highlight the role of regulatory sequences in the 5 0 regulatory region of the Dmt1 gene as binding sites for HIF-1a (Lee et al 1998). However, due to the near absence of the expression of the 1A isoform, no significant changes in total Dmt1 expression were detected, showing the limited adaption possibilities of insulin-producing cells to hypoxic conditions in contrast to other cell types (Carlsson & Palm 2002).…”

Section: Discussionsupporting

confidence: 91%

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Lortz

Schröter

Stückemann

et al. 2014

Journal of Molecular Endocrinology

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Free intracellular ferrous iron (Fe 2C ) is essential for the generation of the extremely toxic hydroxyl radicals, which contribute to b-cell destruction by cytokines. Therefore the expression of the different divalent metal transporter 1 (Dmt1) isoforms and ferritin (Ft) subunits, responsible for iron import and chelation, was analyzed under pro-inflammatory conditions (IL1b alone or together with TNFaCIFNg). The Dmt1 isoforms (1A/1B and CIRE/ KIRE) and the total Dmt1 expression in insulin-producing cells (RINm5F and INS-1E), in primary rat islets and, for comparison, in the neuroendocrine PC12 cell line were quantified by qRT-PCR. In addition, the expression of the light (L-Ft) and heavy Ft (H-Ft) subunits and the mitochondrial Ft isoform (Mtft) in insulin-producing cells under control conditions and after cytokine treatment was estimated. The 1B isoform was the predominant Dmt1 mRNA in all insulin-producing cells, accounting for almost 100% of the 1A/1B isoform expression. For the IRE variants, CIRE expression was higher than KIRE expression. Pro-inflammatory cytokines accelerated the expression of Dmt1 isoforms significantly with an overall 2.5-to 3-fold increase in the total Dmt1 expression. In contrast, the expression of the iron-buffering ferritin subunits L-and H-Ft was unaffected by IL1b and only slightly induced by the cytokine mixture. Mtft expression was also not increased. Dmt1 expression was significantly elevated through pro-inflammatory cytokines, whereas Ft expression was marginally increased. This imbalance between the increased iron transport capacity and the almost unaffected iron storage capacity can foster cytokine-mediated formation of hydroxyl radicals and thus pro-inflammatory cytokine toxicity through elevated free iron concentrations.

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Section: Discussionsupporting

confidence: 91%

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Lortz

Schröter

Stückemann

et al. 2014

Journal of Molecular Endocrinology

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“…DMT1, the principal transport protein for iron and other transition metals, behaves in an analogous fashion to these other essential components involved in iron homeostasis. DMT1 expression is modified by hypoxia in a compensatory manner presumably to help preserve normal iron balance in vivo (11). Figure 3.…”

Section: Discussionmentioning

confidence: 99%

“…Lis et al concludes that expression of the 1A containing species of DMT1 is increased in hypoxic treatment (11). The studies by Mastrogiannaki et al (12) and Shah et al (13) demonstrate that DMT1 exon1A is specifically regulated by HIF-2 but not by HIF-1.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Zhao

et al. 2010

IUBMB Life

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SummaryHypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis, including ceruloplasmin, transferrin, and transferring receptor. Divalent metal transporter 1 (DMT1) is a transmembrane protein that is important in divalent metal ion transport, in particular iron. Although previous studies have provided that DMT1 exon1A is regulated by hypoxia, little is known about the relationship between DMT1 exon1B and hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is stabilized when mammalian cells are subjected to hypoxia. In this study, we have identified a functional hypoxia-response element (HRE) at position of 2327 to 2323 (-ACGTG-) in DMT1 exon1B promoter using a combination of bioinformatics and biological approaches. Both the total cellular iron and ferrous uptake increased after hypoxia, decreased after DMT1 RNA interference. Reactive oxygen species (ROS) were also changed by 1iron responsive element (IRE) DMT1 exon1B overexpression. These findings implicated DMT1 exon1B was a target gene for HIF-1. Hypoxia might affect cellular iron uptake through regulating the expression of DMT1. When iron was present in excess, cells might be damaged by the ROS production. Keywords divalent metal transporter 1; exon1B; hypoxia-inducible factor-1a; hypoxia response element; iron uptake; reactive oxygen species.

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“…The DMT1-1A isoform is expressed mainly in the duodenum and shows the greatest increases in expression in response to hypoxia or iron deficiency (27,28). We mapped 5 candidate HRE elements (2 in the sense and 3 in the antisense orientation) in the human DMT1-1A promoter (Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/JCI38499DS1).…”

Section: Figurementioning

confidence: 99%

HIF-2α, but not HIF-1α, promotes iron absorption in mice

Mastrogiannaki

Matak²,

Keith³

et al. 2009

J. Clin. Invest.

426

376

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HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1α was not necessary for iron absorption, whereas HIF-2α played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2α, to improve iron homeostasis in patients with iron disorders.

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Hypoxia induces changes in expression of isoforms of the divalent metal transporter (DMT1) in rat pheochromocytoma (PC12) cells

Cited by 44 publications

References 33 publications

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

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

HIF-2α, but not HIF-1α, promotes iron absorption in mice

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