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

Leung, Yuk‐Man; Zhu, Wenhui; Loh, Tatt‐Tuck

doi:10.1159/000109483

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…This implicates that a transferrin-related survival effect was independent of iron, of the transferrin protein core, and of the receptor CD71 (Lesnikov et al, 2001). Also, ironindependent growth promotion of HL-60 cells by transferrin was demonstrated (Leung et al, 1993) and transferrin receptor activation with specific antibodies (therefore iron-independent) stimulated tyrosine phosphorylation of TCR and growth in T-cells (Salmeron et al, 1995). In contrast, blocking CD71 by monoclonal antibodies evidenced that transferrin receptor activity is necessary to prevent iron deprivation-induced apoptosis of 38C13 lymphoma cells (Kovar et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

et al. 2003

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The activation of Myc induces apoptosis of human ovarian adenocarcinoma N.1 cells when serum factors are limited. However, the downstream mechanism that is triggered by Myc is unknown. Myc-activation and treatment with the proapoptotic ligands TNFalpha, FasL, and TRAIL induced H-ferritin expression under serum-deprived conditions. H-ferritin chelates intracellular iron and also intracellular iron sequestration by deferoxamine-induced apoptosis of N.1 cells. Supplementation of serum-free medium with holo-transferrin blocked apoptosis of N.1 cells that was induced by Myc-activation or by treatment with TNFalpha, FasL, and TRAIL, whereas apotransferrin did not prevent apoptosis. This suggests that intracellular iron depletion was a trigger for apoptosis and that transferrin-bound iron rescued N.1 cells. Furthermore, apoptosis of primary human ovarian carcinoma cells, which was induced by TNFalpha, FasL, and TRAIL, was also inhibited by holo-transferrin. The data suggest that Myc-activation, FasL, TNFalpha, and TRAIL disturbed cellular iron homeostasis, which triggered apoptosis of ovarian carcinoma cells and that transferrin iron ensured survival by re-establishing this homeostasis.

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Section: Discussionmentioning

confidence: 99%

Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

et al. 2003

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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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“…(1) It has been previously identified as one of the components in serum-free medium formulations, essential for in vitro cell growth. (19) Transferrin may function exclusively as an iron donor in promoting lymphocyte proliferation. (20) Different lines of recent evidence indicate, however, that supplying cells with iron cannot be regarded as the sole explanation of the growth stimulatory effect of Tf.…”

Section: Discussionmentioning

confidence: 99%

“…(20) Different lines of recent evidence indicate, however, that supplying cells with iron cannot be regarded as the sole explanation of the growth stimulatory effect of Tf. (21) Apo-Tf can elevate intracellular free calcium ion level and stimulate mitogenesis in human leukemic HL60 cells, (19) and its addition in serumfree medium can markedly promote DNA synthesis. (19) These effects require, however, the presence of other growth or nutritional factors, that is, insulin, ethanolamine and selenite, in serum-free medium.…”

Section: Discussionmentioning

confidence: 99%

“…(21) Apo-Tf can elevate intracellular free calcium ion level and stimulate mitogenesis in human leukemic HL60 cells, (19) and its addition in serumfree medium can markedly promote DNA synthesis. (19) These effects require, however, the presence of other growth or nutritional factors, that is, insulin, ethanolamine and selenite, in serum-free medium. The data provided in this report describes a Tf h -specific MAb, TRC-2, which is depressive on cell proliferation in serum-free medium but fails to inhibit the binding of Tf h to its receptor.…”

Section: Discussionmentioning

confidence: 99%

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Partial Characterization of the Human Serum Transferrin Epitope Reactive with the Monoclonal Antibody TRC-2

Öztürk

Çirakoğlu

Bermek

2003

Hybridoma and Hybridomics

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A murine monoclonal antibody (MAb) (TRC-2) specific for human serum transferrin (Tf(h)) was developed. This antibody was depressive on cell growth in serum-free medium in the presence of limiting amounts of Tf(h), but it did not inhibit the binding of Tf(h)-alkaline phosphatase (AP) conjugate to the Tf-receptor (TfR) in a cellular enzyme-linked immunosorbent assay (CELISA) system. On the other hand, the immune complex Tf(h)-TRC-2 was implicated to bind to the receptor in indirect CELISA. Moreover, the detectability of Tf(h)-TfR on the cell surface via Tf-bound TRC-2 suggested that the antibody may inhibit the rapid internalization of this complex. To map the TRC-2-specific epitope, Tf(h) was subjected to proteolytic degradation following sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. The treatment with trypsin gave rise to, among others, a fragment of about 42 kDa, which was reactive with TRC-2. Through sequence analysis by automated Edman degradation, the N-terminal sequence of the 42 kDa-tryptic fragment was aligned to the N-terminus of mature transferrin (VPDKTVR). The N-terminal sequence of an immunoreactive CNBr-fragment of about 13 kDa was, in turn, identical with the sequence (NQLRGKK) corresponding to the residues 110-116 on Tf(h).

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

Cited by 6 publications

References 12 publications

Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFα, FasL, TRAIL, or Myc

Regulation of Transferrin Function and Expression: Review and Update

Partial Characterization of the Human Serum Transferrin Epitope Reactive with the Monoclonal Antibody TRC-2

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