Inhibition of heme synthesis decreases transferrin receptor expression in mouse erythroleukemia cells

Abstract

The coordination of transferrin receptor (TfR) expression and heme synthesis was investigated in mouse erythroleukemia (MEL) cells of line 707 treated with heme synthesis inhibitors or in a variant line Fw genetically deficient in heme synthesis. Cells of line 707 were induced for differentiation by 5 mM hexamethylene bisacetamide (HMBA). TfR expression increased in the course of induction, as judged by increased TfR mRNA synthesis, increased cytoplasmic TfR mRNA level, and by the increased number of cellular 125I-Tf binding sites. Addition of 0.1 mM succinylacetone (SA) decreased cellular TfR to the level comparable with the uninduced cells. The decrease was reverted by the iron chelator desferrioxamine (DFO) but not by exogenous hemin. In short-term (1-2 hours) incubation, SA inhibited 59Fe incorporation from transferrin into heme, whereas total cellular 59Fe uptake was increased. A decrease in TfR mRNA synthesis was apparent after 2 hours of SA treatment. Conversely, glutathione peroxidase mRNA synthesis, previously shown to be inducible by iron, was increased by SA treatment. Cells of heme deficient line Fw did not increase the number of Tf binding sites after the induction of differentiation by 5 mM sodium butyrate. SA had no effect on TfR expression in Fw cells. The results suggest that the depletion of cellular non-heme iron due to the increase in heme synthesis maintains a high level of transferrin receptor expression in differentiating erythroid cells even after the cessation of cell division.

Ferrochelatase, glutathione peroxidase and transferrin receptor mRNA synthesis and levels in mouse erythroleukemia cells–mRNA synthesis and levels

“…Both post-transcriptional regulation mediated by intracellular iron concentration-dependent mRNN protein interactions changing the half-life of TW mRNA [8] and the regulation of the rate of transcription [9] are involved in the modulation of TfR number. Conflicting results have been reported concerning the regulation of TfR gene expression by intracellular chelatable iron pool in erythroid cells [6,7,101.…”

Regulation of Transferrin Function and Expression: Review and Update

“…Moreover, the TfR expression in developing erythroid cells is inhibited by heme synthesis inhibitors, suggesting that optimal heme synthesis is required for the receptor expression [41,47]. Interestingly, immunological evidence has indicated that a distinct form of TfRs expresses in the erythroid cells [48], although the origin and the function of this novel form of receptors are still not clear.…”

Inhibition of heme synthesis induces apoptosis in human erythroid progenitor cells

“…Using this experimental system, we demonstrated that several ways of treating these cells, which have in common inhibition of heme synthesis, result in enhanced apoptosis. While 0.1 mmol/L of SA strongly induced apoptosis in human ECFC, it was reported that this concentration of SA did not affect the viability or proliferation of erythroleukemic cells (Ebert et al, 1979;Hradilek et al, 1992). These concentrations of SA were tested in HL-60 cells, a promyelocytic leukemia cell line, and had little effect on cellular viability and the amount of uncleaved DNA (Fig.…”