Invited Symposium: Iron Transport
Lok, CN (Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, Canada)
In proliferating nonerythroid cells the expression of transferrin receptors (TfR), which mediate iron (Fe) uptake from transferrin (Tf), is negatively regulated post-transcriptionally by intracellular Fe through iron responsive elements (IREs) in the 3' UTR of TfR mRNA. IREs are recognized by specific cytoplasmic proteins (IRPs; Fe regulatory proteins) that in the absence of Fe bind to the IREs of TfR mRNA, preventing its degradation. However, our studies suggest a distinct regulation of TfR expression in hemoglobin-synthesizing cells. We demonstrated increased TfR mRNA transcription following induction of erythroid differentiation of murine erythroleukemia (MEL) cells with no increase in IRP-1 activity, or IRP-2 levels. We also found that the human TfR promoter region contains sequences similar to a linked Ets/AP-1 site and GC rich elements, and demonstrated that they play an important role in TfR transcription. Moreover, we have provided evidence that heme is essential for maintaining a normal rate of TfR synthesis in erythroid cells. We showed that heme synthesis inhibitors strongly inhibited TfR expression in hemoglobin-synthesizing cells, but had virtually no effect on the expression of TfR in non-erythroid cells. In addition, 48h-incubation of MEL cells with 5-aminolevulinic acid (ALA, heme precursor) resulted in a dose-dependent increase in TfR mRNA levels. ALA-mediated enhancement of TfR mRNA could be prevented by succinylacetone (an inhibitor of ALA dehydratase), indicating that the effect required the conversion of ALA into heme. Control and ALA-treated MEL cells contained identical levels of active IRP-1, suggesting that endogenous heme may stimulate TfR expression by a transcriptional mechanism. In conclusion, erythroid precursors fullfil the enormous iron demand for hemoglobin synthesis by up-regulating levels of TfR and, in turn, this 'overexpression' is in part achieved by high heme levels.
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|Ponka, P; Lok, CN; (1998). The Control of Transferrin Receptor Expression in Erythroid Cells. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/templeton/ponka0887/index.html|
|© 1998 Author(s) Hold Copyright|