Characterization of a transferrin-independent uptake system for iron in HeLa cells.

Sturrock, Anne; Alexander, James; Lamb, Jamie E.; Craven, Catherine; Kaplan, Jerry

doi:10.1016/s0021-9258(19)39745-5

Cited by 165 publications

(14 citation statements)

References 34 publications

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“…The mechanisms that can be proposed to explain NTBI uptake modulation in response to Al exposure may involve the appearance of previously cryptic carriers [10] or the increase in the synthesis of transport proteins since Al proved to be able to translocate into the nucleus and interact with genetic material [29,30]. An alternative explanation is related to Al interference with the signaling pathway of calcium homeostasis [31], thus affecting NTBI transport since this is a calcium-dependent mechanism [9,10,25]. On the other hand, the disturbance of the dynamic regulation of essential events occurring at the cell membrane level, such as metal transport, could be explained by significant changes in cell morphology and structural protein organization caused by the presence of Al in the cellular environment [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

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Aluminum exposure affects transferrin-dependent and -independent iron uptake by K562 cells

Pérez¹,

Pregi²,

Vittori³

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Aluminum (Al) and iron (Fe) share several physicochemical characteristics and they both bind to transferrin (Tf), entering the cell via Tf receptors (TfR). Previously, we found similar values of affinity constant for the binding of TfR to Tf carrying either Al or Fe. The competitive interaction between both metals prevented normal Fe incorporation into K562 cells and triggered the upregulation of Fe transport. In the present work we demonstrated that Al modified Fe uptake without affecting the expression of Tf receptors. Both TfR and TfR2 mRNA levels, evaluated by RT-PCR, and TfR antigenic sites, analyzed by flow cytometry, were found unchanged after Al exposure. In turn, Al did induce upregulation of non-Tf bound Fe (NTBI) uptake. This modulation was not due to intracellular Fe decrease since NTBI transport proved not to be regulated by Fe depletion. Unlike its behavior in the presence of Tf, Al was unable to compete with NTBI uptake, suggesting that both metals do not share the same alternative transport pathway. We propose that Al interference with TfR-mediated Fe incorporation might trigger the upregulation of NTBI uptake, an adaptation aimed at incorporating the essential metal required for cellular metabolism without allowing the simultaneous access of a potentially toxic metal.

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Section: Discussionmentioning

confidence: 99%

“…In addition to the well-described Tf-dependent pathways, many studies have demonstrated the existence of an uptake system involving non-transferrin bound iron (NTBI) [9][10][11][12]. Even though the function and regulation of this transport have not been completely elucidated yet, at least two mechanisms have been reported.…”

Section: Introductionmentioning

confidence: 99%

Aluminum exposure affects transferrin-dependent and -independent iron uptake by K562 cells

Pérez¹,

Pregi²,

Vittori³

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In order to investigate transferrin-independent iron transport via Nramp2 expressed on the plasma membrane, we minimized the possible contamination by transferrin in our experiments. This was done by incubating the transfected cells first in serum-free medium to deplete transferrin and at pH 5.5, a pH value at which transferrin binds iron poorly and is not internalized by the cells [18]. The stronger Nramp2 expression on the endosomal membrane (Figure 5) might result in an even higher level of iron uptake via the transferrin-dependent pathway.…”

Section: Monkey Nramp2a and Nramp2b Demonstrate A Similar Ability In The Transferrin-independent Uptake Of Ironmentioning

confidence: 99%

“…These previous studies seem to imply that Nramp2 could be involved in both transferrin-dependent and transferrin-independent transport of iron into the cell. There have also been some contradictory reports regarding the necessity for both a reduction of iron from the ferric to ferrous form and the presence of Ca# + for the transferrin-independent iron-uptake process to occur [18][19][20]. Clearly, for a better understanding of its roles in iron uptake, the functions and properties of Nramp2 need to be further characterized.…”

Section: Introductionmentioning

confidence: 99%

Heterologous expression, functional characterization and localization of two isoforms of the monkey iron transporter Nramp2

Zhang¹,

Lee²,

Wang³

et al. 2000

Biochem. J.

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Natural resistance-associated macrophage protein 2 (Nramp2) has been suggested to be involved in transferrin-independent iron uptake. Two isoforms of the Nramp2 gene generated by alternative splicing of the 3' exons were identified in mouse, rat and human, but it is unclear if they perform distinct functions. To rationalize our previous work, which indicated an increase in iron deposition in a Parkinsonian monkey brain, two monkey Nramp2 isoforms were isolated for a comparative study to assess their relative iron-uptake abilities, tissue distribution and subcellular localization. The monkey Nramp2 isoforms, 2a and 2b, exhibit approx. 98% identity at the amino acid level when compared with the human homologues. The Nramp2a transcript contains a canonical iron-responsive element (IRE), whereas that of Nramp2b lacks the IRE motif in the 3' untranslated region. By reverse transcriptase (RT)-PCR, the mRNAs of both isoforms were detected in all tissues examined. The amino acid differences at the C-terminus neither affected the protein expression levels in HEK-293T and COS-7 cells nor altered the subcellular localization and tissue distribution of the isoforms. Similar levels of iron uptake were detected in the HEK-293T cells transfected with either the Nramp2a or 2b gene, and a reduction of iron from the ferric (Fe(3+)) to the ferrous (Fe(2+)) state is necessary before transport can take place. However, this transferrin-independent uptake of iron into the cells is not a Ca(2+)-dependent process.

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“…Iron transport across endosomal membranes is thought to involve the reduction of Fe 3 ϩ to Fe 2 ϩ (Nunez et al, 1990;Watkins et al, 1992;Oshiro et al, 1993) but the Fe-translocating machinery has yet to be defined. Cells can also translocate non-Tf-bound Fe across the plasma membrane (Sturrock et al, 1990;Inman and Wessling-Resnick, 1993); in fact, this process may play an important role in pathologic states such as hemochromatosis wherein Tf reaches saturation. The characteristics of Tf-independent transport also suggest a role for a ferrireductase activity (Inman et al, 1994;Jordan and Kaplan, 1994;Randell et al, 1994;Riedel et al, 1995), but the relationship between cell surface and endosomal Fe membrane carriers is unknown.…”

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confidence: 99%

Functional Expression Cloning and Characterization of SFT, a Stimulator of Fe Transport

Gutiérrez

Rivera

et al. 1997

The Journal of Cell Biology

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A stimulator of Fe transport (SFT) was identified by functional expression cloning in Xenopus oocytes. SFT-mediated transport has properties defined for transferrin-independent Fe uptake, but its cytolocalization in recycling endosomes and the observed stimulation of transferrin-bound Fe assimilation indicate a key role in intracellular Fe membrane transport as well. SFT has six predicted transmembranous domains and a functionally important RExxE motif that resembles domains involved in yeast Fe transport and Fe-binding by ferritin L-chains. The observation that SFT oligomerizes, along with other structural and mechanistic features, suggests it may be a member of either the ATP-binding cassette or cation diffusion facilitator families. The 3′ untranslated region of SFT contains a translation inhibitory element and inhibition of SFT expression in Xenopus oocytes was found to be relieved by coinjection of transcripts from other defined cDNAs that are also described in this report. SFT is the first component of the mammalian Fe membrane transport machinery to be identified.

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Characterization of a transferrin-independent uptake system for iron in HeLa cells.

Cited by 165 publications

References 34 publications

Aluminum exposure affects transferrin-dependent and -independent iron uptake by K562 cells

Aluminum exposure affects transferrin-dependent and -independent iron uptake by K562 cells

Heterologous expression, functional characterization and localization of two isoforms of the monkey iron transporter Nramp2

Functional Expression Cloning and Characterization of SFT, a Stimulator of Fe Transport

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