Regulation of Transferrin Function and Expression: Review and Update

Abstract

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.

Immunophenotypic clustering of myelodysplastic syndromes

“…The expression of CD71, which is the receptor for the iron transporter transferrin, is regulated by iron depletion. 19,20 RARS is characterized by DNA mutations of mitochondria resulting in an abnormal metabolism of iron and a defect in its incorporation in the heme structures and in the cytochrome c of the respiratory chain of mitochondrion. 21 This raises the question of whether the up-regulation of CD71 expression on CD45 hi /SS hi granulocytes of patients with RARS could be an immunophenotypic reflection of the defect in iron metabolism in these cells originated from the BM precursor.…”

Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors

“…The mass of liver TfR remained constant in most experimental conditions studied here, except after phlebotomies. The latter is characterized by tissue iron deficiency and thus increased expression of TfR in all cell types [2,27]. On the other hand, iron-restricted erythropoiesis or functional iron deficiency as produced by erythroid regeneration after thiamphenicol-induced red cell aplasia may cause a more modest increase in liver TfR expression despite presumably maintained iron stores.…”

“…Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor (TfR) [1][2][3]. The functional receptor is composed of two monomers linked by two disulfide bridges to form a molecule of 190,000 Da.…”

The major histocompatibility complex-encoded class I-like HFE abrogates endocytosis of transferrin receptor by inducing receptor phosphorylation

“…[6][7][8][9] Because the levels of TfR expression are functionally linked to the requirements of the cells for iron, TfR plays an essential role in cellular iron metabolism. [10][11][12][13] 8 May 2000 ment and an abnormal iron homeostasis. 14 Upon binding to the diferric transferrin (Tf), TfR-Tf is endocytosed into endosomes, where the low pH causes Tf to release its iron into the cytosol.…”