Transferrin-receptor-independent but iron-dependent proliferation of variant Chinese hamster ovary cells

Chan, Roxanne Y. Y.; Ponka, Prem; Schulman, Herbert M.

doi:10.1016/0014-4827(92)90082-j

Cited by 45 publications

(23 citation statements)

References 54 publications

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“…As compared to normal cells, neoplastic cells have significantly higher levels of TfR [51] and, thus, take up iron from transferrin rapidly [52,53]. Several cell lines lacking TfR have been produced [54,55] and they grow as fast as the parental cells [56]. Similarity, our results suggest that As-8w-HOS and As-T-HOS cells are capable of incorporating iron through non-TfR pathway(s).…”

Section: Discussionsupporting

confidence: 70%

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenitetransformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.

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Section: Discussionsupporting

confidence: 70%

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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“…Evidence for the presence of this additional pathway is provided by the isolation of several cell lines that lack transferrin receptors but survive and display growth comparable to parental cell lines (47,48). In addition, even in the absence of transferrin receptors, the CHO-TRVb cell line demonstrates a basal level of transferrin binding as well as uptake of iron from this transferrin (11,15). In a separate study, homozygous TfR knock-out mice (Tfr Ϫ/Ϫ ) embryos survived until E 8.5-12.5, and a few did not reveal any symptoms of tissue edema or necrosis characteristic to these embryos (18).…”

Section: Discussionmentioning

confidence: 99%

“…(13,14). Although TfR-mediated iron uptake is the major pathway for iron acquisition, several studies have indicated that additional mechanisms independent of known TfRs exist; however, these have not been well characterized (15)(16)(17)(18). GAPDH was previously considered to be an abundantly present cytosolic protein with a key role in energy metabolism.…”

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confidence: 99%

The Macrophage Cell Surface Glyceraldehyde-3-phosphate Dehydrogenase Is a Novel Transferrin Receptor

Raje¹,

Kumar²,

Harle

et al. 2007

Journal of Biological Chemistry

125

111

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The reticuloendothelial system plays a major role in iron metabolism. Despite this, the manner in which macrophages handle iron remains poorly understood. Mammalian cells utilize transferrin-dependent mechanisms to acquire iron via transferrin receptors 1 and 2 (TfR1 and TfR2) by receptor-mediated endocytosis. Here, we show for the first time that the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is localized on human and murine macrophage cell surface. The expression of this surface GAPDH is regulated by the availability of iron in the medium. We further demonstrate that this GAPDH interacts with transferrin and the GAPDHtransferrin complex is subsequently internalized into the early endosomes. Our work sheds new light on the mechanisms involved in regulation of iron, vital for controlling numerous diseases and maintaining normal immune function. Thus, we propose an entirely new avenue for investigation with respect to transferrin uptake and regulation mechanisms in macrophages.Iron is an essential nutrient for all organisms as a constituent of hemoproteins and iron-sulfur proteins. In addition it is also a critical component of functional groups of several proteins involved in vital housekeeping functions. Cells of the immune system require iron for their normal functions such as proliferation, activation, and maturation of lymphocytes (1-5). Iron is also essential for macrophage-mediated cytotoxicity by the production of highly toxic hydroxyl radicals (6, 7). The mononuclear phagocyte system is composed of monocytes, macrophages, and their precursor cells, which play a vital role in iron metabolism by removing effete erythrocytes and recycling iron. These cells also acquire iron via the receptor-mediated uptake of transferrin and the hemoglobin scavenger receptor (8). Practically all extracellular iron circulating in the plasma is bound to transferrin, an abundant protein with high affinity for iron. Two mammalian transferrin receptors TfR1 4 and TfR2 have so far been characterized. Both these receptors are cell surface transmembrane, glycoproteins (9). Unlike TfR1, TfR2 is not regulated by intracellular iron concentrations. This receptor also binds transferrin in manner similar to TfR1, but with a 25-fold lower affinity (10,11,12). Iron uptake from transferrin involves binding to its receptors followed by internalization to the early endosomes. (13, 14). Although TfR-mediated iron uptake is the major pathway for iron acquisition, several studies have indicated that additional mechanisms independent of known TfRs exist; however, these have not been well characterized (15-18). GAPDH was previously considered to be an abundantly present cytosolic protein with a key role in energy metabolism. However, recent evidence has proved that it functions as a moonlighting protein in both prokaryotic and eukaryotic cells, often differentially localized within the cell (19 -21). It is of interest to note that in Staphylococcus aureus, cell wall-associated GAPDH had previously been identified as a trans...

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“…A reduction in the initial rate and steadystate levels of transferrin accumulation was consistent which possessed no detectable transferrin binding sites but were still able to accumulate iron by an NTR-mediwith the decline in the number of TR, demonstrating that the inhibition of iron uptake was completely at-ated process. 21 Similarly, an antibody to the TR directly inhibited the TR-mediated uptake of transferrin and tributable to the reduction in the level of receptor expression, and there was no alteration to the recycling iron by rat hepatocytes, but there was no effect on the second process. The uptake of transferrin at 37ЊC reflects total cellular labeled and unlabeled transferrin for the TR-binding sites.…”

Section: P0e$$0043mentioning

confidence: 98%

Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression

1996

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The hepatic uptake of transferrin-bound iron by aIron is required for the synthesis of many heme and nontransferrin receptor (NTR)-mediated process was non-heme proteins and enzymes necessary for cellular investigated using the human hepatoma cell line HuH7. growth and metabolism. Most cells take up iron from Because HuH7 cells also acquire iron from transferrin serum transferrin by a transferrin receptor (TR)-mediby a receptor (TR)-mediated process, TR expression was ated process. Hepatocytes, in addition to their own inhibited by transfecting the cells with a plasmid con-need for iron, are also an important site of iron storage. taining human TR complementary DNA in antisense ori-They acquire iron by many pathways, including TRentation relative to a human cytomegalovirus promoter/ mediated uptake of iron from transferrin, 1 iron taken enhancer element. Cell clones were obtained that exup by from desialylated transferrin through the asiapressed a 50% to 60% reduction in cell surface TR, leadloglycoprotein receptor, 2 iron carried by ferritin, 3,4 and ing to a corresponding decrease in transferrin and iron uptake compared with wild-type cells. Uptake of trans-transferrin-iron secured by a non-transferrin receptorferrin by a second process was nonsaturable and not mediated process 5 (NTR). The TR-mediated uptake of inhibited by a 100-fold excess of unlabeled transferrin. transferrin-iron has been studied extensively, particuThe amounts of transferrin taken up by the wild-type larly in the developing erthyroid cell. 6 The receptorand antisense cells by this process were similar, showing mediated process involves the binding of transferrin to that it did not involve TR. The proteolytic enzyme Pro-a cell surface TR, internalization of the transferrin-TR nase reduced the uptake of transferrin, suggesting that complex into an endocytotic vesicle, the release of iron the NTR-mediated process entailed the nonsaturable from transferrin, and transport into the cell cytosol and binding of transferrin to plasma membrane proteins.the recycling of the apotransferrin-TR complex to the This process, like the TR-mediated one, involved the incell surface, where the apotransferrin is released.7 By ternalization and recycling of transferrin, leading to accumulation of iron with time. Iron uptake mediated by contrast, the other processes of iron delivery, especially NTR process was saturable and displaced by 100-fold the TR-independent uptake of transferrin-iron, have excess unlabeled transferrin and reduced by weak bases not been well characterized. and metabolic inhibitors. Therefore, the NTR-mediatedIn an earlier study from this laboratory, data were process entailed transferrin adsorption to membrane-presented indicating that the uptake of iron from transbound proteins, internalization, and release of iron from ferrin by isolated hepatocytes was dependent on the transferrin by a pH-dependent step followed by the in-extracellular transferrin concentration. Received July 13, 1995; accepted December 29, 1995. ical importance of...

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Transferrin-receptor-independent but iron-dependent proliferation of variant Chinese hamster ovary cells

Cited by 45 publications

References 54 publications

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Altered iron homeostasis involvement in arsenite-mediated cell transformation

The Macrophage Cell Surface Glyceraldehyde-3-phosphate Dehydrogenase Is a Novel Transferrin Receptor

Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression

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