Studies on the mitogenic effect of transferrin by membrane signal transduction

Leung, TM; Pl, Lim; Loh, Tatt‐Tuck

doi:10.1038/cr.1990.22

Cited by 3 publications

(3 citation statements)

References 10 publications

(16 reference statements)

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“…Previously we also observed that in the rat hepatoma RH-35 cell line diferric transferrin elicited a rise in [Ca2+]j [8], Our data here show that the ironfree form of transferrin, apotransferrin, could stimulate a small calcium influx in HL60 cells. Due to equipment limitation, we were not able to measure [Ca2+]j by the ratio (dual excitation wavelength) method, which is more sensitive and accurate than the single excita tion wavelength method.…”

Section: Discussionsupporting

confidence: 49%

“…Recently, we had shown that binding of transferrin to rat hepatoma RH35 cells elicit ed a transient rise in the following intracellu lar messengers: intracellular calcium, inositol-1, 4, 5-trisphosphate and intracellular pH, a phenomenon very similar to the transduction of the proliferative (growth) signals mediated by growth factor-receptor interactions [8]. Also in chick embryonic retinal neurons, transferrin causes an elevation in intracellular calcium level and membrane depolarization [9].…”

Section: Introductionmentioning

confidence: 99%

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Apotransferrin Can Elevate Intracellular Free Calcium Ion and Stimulate Mitogenesis in Human Leukemic HL60 Cells

Leung¹,

Zhu²,

Loh³

1993

Neurosignals

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In order to resolve the question whether or not transferrin could have a growth-promoting effect on cells independent of its action in iron transport, we investigated the effect of the iron-free form of transferrin, apotransferrin on cell activation and proliferation in the human leukemic HL60 cell line. Within a minute of its addition to HL60 cells, apotransferrin caused a rise in intracellular free calcium concentration ([Ca²⁺]_i) in a dose-dependent manner and the higher the apotransferrin, the quicker it was to attain the calcium peak, showing the physiological characteristics of an agonist-induced [Ca²⁺]_i elevation. The source of calcium appears to be extracellular since this signal could be abolished by nickel or when the reaction was carried out in calcium-free medium. Addition of apotransferrin in the serum-free medium could markedly promote DNA synthesis whereas addition of iron citrate could not. However, apotransferrin could not sustain cell proliferation and hypertrophism without other growth or nutritional factors. Antitransferrin receptor antibody inhibited the growth of HL60 cells cultured in serum-free medium supplemented with transferrin and insulin in a dose-dependent manner, whereas addition of ferric citrate could not reverse cell growth. Generation of the calcium signal probably reflects the initiation of the cell activation processes which could culminate into mitogenesis. Hence, our results suggest that apotransferrin, not iron, is bioactive in HL60 cells.

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Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Apotransferrin Can Elevate Intracellular Free Calcium Ion and Stimulate Mitogenesis in Human Leukemic HL60 Cells

Leung¹,

Zhu²,

Loh³

1993

Neurosignals

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“…Besides, a growthpromoting effect of transferrin/iron independent of its nutritional role has been postulated and putative mitogenic signals generated by the TfR have been reported. The evidence for these elusive mechanisms include stimulation of the sodium/proton antiport activity through a reduction of diferric transferrin by a transmembrane electron transport system in Hela cells [102], elevation of intracellular calcium elicited by apotransferrin in HL-60 leukemic cells [103,104], activation of protein kinase C gene transcription by iron transferrin in CCRF-CEM leukemic cells [105] and induction of protein phosphorylation by an anti-TfR antibody [106]. However, it should be noted that a correlation between the proliferation rate of normal or malignant cells and the expression of the TfRs, though frequently observed, is not always apparent [107].…”

Section: Proliferating Cells (Eg Activated Lymphocytes and Canceroumentioning

confidence: 99%

Regulation of Transferrin Function and Expression: Review and Update

Lok¹,

Loh²

1998

Biol Signals Recept

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The cellular iron uptake is a precisely controlled process to fulfill the iron demand for the synthesis and functions of a variety of iron-containing proteins, and one of the main molecules involved is the transferrin receptor (TfR), which mediates the uptake process via the transferrin cycle. The TfR expression is tightly regulated by factors such as intracellular iron level, cell proliferation or erythropoiesis at levels of receptor recycling, transcriptional or posttranscriptional control. The iron-regulatory protein/iron-responsive element system has been widely used to explain changes in receptor expression during iron loading or depletion, oxidative stress and nitric oxide stimulation. On the other hand, transcriptional control of TfR expression appears to be more important in erythroid differentiation and general cell proliferation. There is also an increasing awareness of the clinical application and experimental therapeutics based on the TfR functioning and expression. In this review, we attempt to provide a concise account of the studies of TfR structure and function as well as those areas that have not been reviewed in depth, in particular, tissue-specific regulation of TfR, the molecular mechanisms of TfR expression, and the use of TfR as diagnostic and therapeutic tools. The regulation of TfR expression in various tissues is related to its specific cellular iron requirements. Hemoglobin-synthesizing cells exhibit distinct features of iron metabolism and TfR expression as compared to most non-erythroid cells which synthesize a much lower amount of heme. For most non-erythroid cells, iron can regulate the TfR expression in a reciprocal manner through modulating the stability of the receptor mRNA whereas in hemoglobin-synthesizing cells, the TfR expression is independent of the cellular iron loading. In spite of a wide heterogeneity in the way receptor redistribution is in response to various stimuli, regulation of the constitutive expression of TfR is one of the ways of regulating the cellular iron uptake. This expression operates on both transcriptional and posttranscriptional levels. In general, factors related to cell growth and differentiation operate on the gene transcription level, whereas iron regulates the fate of the mature mRNA.

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Cellular and molecular mechanisms of glioma growth control

Chirasani¹

2009

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Studies on the mitogenic effect of transferrin by membrane signal transduction

Cited by 3 publications

References 10 publications

Apotransferrin Can Elevate Intracellular Free Calcium Ion and Stimulate Mitogenesis in Human Leukemic HL60 Cells

Apotransferrin Can Elevate Intracellular Free Calcium Ion and Stimulate Mitogenesis in Human Leukemic HL60 Cells

Regulation of Transferrin Function and Expression: Review and Update

Cellular and molecular mechanisms of glioma growth control

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