Invited Symposium: Iron Transport



Transcriptional regulation of transferrin receptor expression during erythroid differentiation

Lack of correlation between IRP-1 binding activities and transferrin receptor expression in erythroid cells

Role of heme in the transferrin receptor expression



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The Control of Transferrin Receptor Expression in Erythroid Cells

Ponka, P (Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, Canada)
Lok, CN (Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, Canada)

Contact Person: Prem Ponka (mdpp@musica.mcgill.ca)


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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Presentation Number SAponka0887
Keywords: iron, transferrin recep, erythroid cells, heme synthesis

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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