Regulation of Transferrin Function and Expression: Review and Update

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.