Rat transferrin gene expression: tissue-specific regulation by iron deficiency.

Idzerda, Rejean L.; Huebers, Helmut A.; Finch, Clement A.; McKnight, G. Stanley

doi:10.1073/pnas.83.11.3723

Cited by 179 publications

(85 citation statements)

References 34 publications

(40 reference statements)

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“…This was challenged because humans with atransferrinemia develop iron-overloading rather than iron deficiency [26]. Neither transferrin nor transferrin receptors could be demonstrated in the microvilli of duodenal mucosal cells [27,28], the gene for transferrin was not expressed in intestinal mucosa cells [29], and the absorption of several divalent metal cations which do not bind transferrin in vivo varied inversely with the state of iron repletion in animals. During the past decade two pathways were identified that appeared to facilitate the uptake of dietary inorganic iron into intestinal absorptive cells.…”

Section: Discussionmentioning

confidence: 99%

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

et al. 2003

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There are two pathways for inorganic iron uptake in the intestine, the ferric pathway, mediated by the key protein mobilferrin, and the ferrous pathway, mediated by DMT-1. Previous studies reported that the amount of DMT-1 increased in the intestinal mucosa in iron deficiency and the increase was seen in the apical portion of the villus of the duodenal mucosa. Mobilferrin did not quantitatively increase but became localized at the cell membrane. However, studies on fresh tissue have not previously been performed and the localization to the microvillae has not been demonstrated. In order to more definitively localize these proteins immunofluorescent and electron microscopic studies were undertaken. Samples were also subjected to biochemical analysis and Western analysis. In iron-deficient animals both DMT-1 and Mobilferrin were concentrated in the apical surface of the villae. Electron microscopy revealed that the majority of this increase in the amount of these proteins near the luminal surface was due to increased binding of the proteins to mucin in vesicles near the surface. A significant portion of the iron transport proteins was localized in the goblet cells and outside the cell in the luminal mucin, as demonstrated by immunofluorescence, electron microscopy, and isolation of the mucin by cesium chloride gradient centrifugation and Western analysis. A new model for the transport of metal ions was suggested. The metal transport proteins travel from vesicles inside the cell out to the lumen mucin. This increases the surface area and allows a greater portion of the lumen contents to be exposed to the binding proteins. Once the metal is bound to the externalized protein it is internalized into the cell. This explains many of the unique properties of the iron-binding proteins and suggests that it may be a more general model for the absorption of other nutrients. Am. J. Hematol. 74:32-45, 2003.

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Section: Discussionmentioning

confidence: 99%

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

et al. 2003

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“…Lactoferrin (LF) is a multifunctional protein belonging to the transferrin family. The levels of transferrin have been shown to increase in iron deficiency anemia [5,6]. Additionally, incidents of bleeding in cancer patients can result in iron deficiency anemia, which subsequently increases the levels of lactoferrin [7–9].…”

Section: Introductionmentioning

confidence: 99%

Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia

et al. 2018

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Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development. However, the role of pep27 gene, belonging to the vancomycin-resistance locus (vncRS operon), in virulence, is largely unknown. This study demonstrates that transferrin in the host serum reduces the survival of the host during S. pneumoniae infections in mice. The exposure of the pneumococcal D39 strain to lactoferrin induced the vncRS operon, lysis, and subsequent in vivo cytokine production, resulting in lung inflammation. However, these responses were significantly attenuated in pneumococci harboring a mutation in pep27. Mechanistically, the VncS ligand, identified as lactoferrin, induced the vncRS operon and increased the in vivo mortality rates. Thus, serum-induced activation of vncRS plays an essential role in inducing pneumonia.

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“…The tissue specificity of transferrin gene expression has been quantified in several species. In rats, for example, transferrin mRNA accumulates to a level of 6,500 molecules per cell in liver and roughly 100 molecules per cell in brain and testis, whereas most other tissues have less than 12 molecules per cell (18). Transferrin gene expression has also been studied during fetal development, revealing a pattern of expression that deviates dramatically from the adult pattern.…”

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confidence: 99%

Expression from the transferrin gene promoter in transgenic mice.

et al. 1989

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Transferrin is an iron-binding protein that is expressed as a major product in liver and secreted into the plasma. To study the tissue-specific regulatory regions of this gene, the genomic mouse transferrin (mTf) gene was cloned and characterized by partial sequence analysis and Si nuclease mapping of the transcriptional start site. Fusion genes containing the transferrin gene promoter and 5'-flanking sequences were ligated to the human growth hormone (hGH) gene and used to produce transgenic mice. A deletion construct containing the -581 to +50 region of the transferrin gene was sufficient to direct a high level of liver-specific expression resembling endogenous transferrin gene expression. Deletion to -139 base pairs of 5'-flanking sequence gave a construct which retained liver specificity, but the magnitude of expression decreased severalfold. These results demonstrate the presence of a liver-specific transcriptional element between -139 and +50 and suggest the presence of a distal element between -581 and -139 that can further increase expression. Surprisingly, fusion constructs containing -3 kilobase pairs (kb) of 5'-flanking sequence gave higher levels of mRNA in nonhepatic tissues than did either the -581 or -139 construct. Further studies indicated that the high levels of circulating hGH in these transgenic mice specifically induced the endogenous transferrin and albumin genes in liver and also stimulated the normally low levels of expression of the endogenous transferrin gene in brain, heart, kidney, and muscle. A mutated hGH gene that does not produce active growth hormone was fused to the -3-to +50-kb transferrin sequences to produce the -3-kb mTf-hGX construct. A liver-specific pattern of expression was observed in transgenic mice harboring the -3-kb mTf-hGX construct, and this mutated transgene was shown to be induced four-to sevenfold by either bovine or human growth hormone. These results demonstrate the presence of a growth hormone-responsive element between -3 and +50 kb in the 5'-flanking region of the mTf gene promoter.

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Rat transferrin gene expression: tissue-specific regulation by iron deficiency.

Abstract: Rats raised on a low-iron diet were used as a model system for investigating the regulation of transferrin gene expression by iron deficiency. We quantitated transferrin

Cited by 179 publications

References 34 publications

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia

Expression from the transferrin gene promoter in transgenic mice.

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