Control of heme synthesis during Friend cell differentiation: Role of iron and transferrin

Laskey, Jennifer; Ponka, Prem; Schulman, Herbert M.

doi:10.1002/jcp.1041290209

Cited by 47 publications

(16 citation statements)

References 40 publications

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“…HO-1 could interfere with the formation of heme and; therefore, we tested the integrity of heme biosynthesis by supplying cells with 59 Fe-salicylaldehyde isonicotinoyl hydrazone ( 59 Fe-SIH), a membrane-permeable iron chelate that has the ability to supply iron for ferrochelatase [22][23][24] via bypassing the physiological transferrinTfR pathway. There was no difference in iron incorporation into heme between MELHO-1 and control cells when the physiological iron delivery pathway was bypassed using 59 Fe-SIH ( Figure 3D).…”

Section: Ho-1 Overexpression Decreases Tfr Levels and Iron Uptake In mentioning

confidence: 99%

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Garcia-Santos

Schranzhofer

Horváthová

et al. 2014

Blood

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Key Points• Heme oxygenase-1 levels increase during erythroid differentiation.• Heme oxygenase-1 actively participates in maintaining appropriate hemoglobinization rates.Heme is essential for the function of all aerobic cells. However, it can be toxic when it occurs in a non-protein-bound form; cells maintain a fine balance between heme synthesis and catabolism. The only physiological mechanism of heme degradation is by heme oxygenases (HOs). The heme-inducible isoform, HO-1, has been extensively studied in numerous nonerythroid cells, but virtually nothing is known about the expression and potential significance of HO-1 in developing red blood cells. We have demonstrated that HO-1 is present in erythroid cells and that its expression is upregulated during erythroid differentiation. Overexpression of HO-1 in erythroid cells impairs hemoglobin synthesis, whereas HO-1 absence enhances hemoglobinization in cultured erythroid cells. Based on these results, we conclude that HO-1 controls the regulatory heme pool at appropriate levels for any given stage of erythroid differentiation. In summary, our study brings to light the importance of HO-1 expression for erythroid development and expands our knowledge about the fine regulation of hemoglobin synthesis in erythroid cells. Our results indicate that HO-1 plays an important role as a coregulator of the erythroid differentiation process. Moreover, HO-1 expression must be tightly regulated during red blood cell development. (Blood.

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Section: Ho-1 Overexpression Decreases Tfr Levels and Iron Uptake In mentioning

confidence: 99%

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Garcia-Santos

Schranzhofer

Horváthová

et al. 2014

Blood

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“…In liver cells, as well as other cell types, addition of ALA or ALA plus iron results in the net accumulation of heme [54][55][56]. Thus, if heme is a significant direct inducer of ferritin synthesis, we would ex pect to see a stimulatory effect of ALA on the ability of inorganic iron to stimulate ferritin synthesis due to enhancement of heme for mation.…”

Section: Role Of Iron Source In Regulation Of Ferritin Mrna Translationmentioning

confidence: 99%

“…In addition use was made of 5-aminolevulinate (ALA) the first committed precursor of heme. Addition of ALA to cells can stimulate heme accumulation [54][55][56]. Ferric pyridoxal isonicotinoyl hydrazone (Fe PIH) can donate iron to the intracellular iron pool more extensively than diferric transferrin [66].…”

Section: Role Of Iron Source In Regulation Of Ferritin Mrna Translationmentioning

confidence: 99%

Translational Regulation of Ferritin Synthesis by Iron

Eisenstein

Munro²

1990

Enzyme

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This review starts with a description of certain features of mammalian ferritins and their DNA and RNA structures relevant to translational control of ferritin synthesis. Although the amino acid sequences of the two ferritin subunits (H and L) diverge in about 50% of the coding region, their five a-helices and the exon sizes of their genes are compatible with the proposition that they diverged from a single ancestral gene. Of particular note is their long 5'-untranslated regions (5'UTRs) which include a 28-nucleotide sequence almost completely identical in the H- and L-subunits of a range of species. This motif near the cap region of the 5'-UTR, which forms a specific stem-loop structure, provides for regulation of the translation of H- and L-ferritin mRNAs. When intracellular levels of chelatable iron are not in excess, a large reserve of H- and L-mRNAs is present in the cell sap, restrained from translation by a protein with an M(r) of about 90-100,000 which binds to the stem-loop structure. When excess iron floods the cytosol, this protein/RNA complex appears to dissociate and the 40S ribosome subunit is now able to initiate ferritin protein synthesis so that the dormant mRNAs become active and are transferred to the polyribosomes. The mechanism whereby the binding protein is regulated in response to iron is currently under investigation. The regulatory protein occurs in the cell sap and is present in several interchangeable forms which appear to differ in the redox state of specific sulphydryls within the protein. Under some circumstances, the abundance of these forms appears to be altered by intracellular iron status. It is unclear how iron influences binding of the regulatory protein to ferritin mRNA. Some investigators consider that iron binds in the form of heme to the regulatory protein, for which they offer in vitro evidence. We have examined the role of heme versus inorganic chelatable iron in the regulation of ferritin and heme oxygenase synthesis in rat fibroblasts and hepatoma cells. By manipulating the flow of iron between the intracellular chelatable iron and heme iron pools we have concluded that chelatable iron can act as a regulator of ferritin synthesis in a manner which is independent of heme formation. This conclusion does not exclude a role for heme in some specialized cell types.

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“…Aminolevulinic acid synthase 1 (Alas1) has been proposed as the rate-limiting enzyme in heme synthesis in non-erythroid cells. In contrast, in erythroid cells, intracellular iron supply, rather than ALAS activity, limits the rate of heme synthesis (42). Therefore, the contribution of increased Alas2 and Fech expression to enhanced heme and hemoglobin biosynthesis may be less significant than the contribution of enhanced TfR1 expression.…”

Section: -Aza-cdr Stimulates Heme Synthesis By C-mycmentioning

confidence: 98%

5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes

Ning

Liu

et al. 2011

Journal of Biological Chemistry

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The hypomethylating agent 5-aza-2-deoxycytidine (5-aza-CdR) and its derivatives have been successfully used for the treatment of myelodysplastic syndromes, and they frequently improve the anemia that usually accompanies these disorders. However, the molecular mechanisms underlying this action remain poorly understood. In this study, we used two erythroid models, murine erythroid leukemia cells and erythroid burst-forming unit-derived erythroblasts, to show that 5-aza-CdR induced erythroid differentiation and increased the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech), thereby increasing iron uptake and heme biosynthesis. We have identified new regulatory E-boxes that lie outside of CpG islands in the TfR1 and Fech promoters, and the methylation status of these sites can be altered by 5-aza-CdR treatment. This in turn altered the binding of the transcription factor c-Myc to these promoter elements. Furthermore, 5-aza-CdR promoted the nuclear translocation of c-Myc and its binding to Max to form functional complexes. The coordinated actions of 5-aza-CdR on the methylation status of the target genes and in stimulating the nuclear translocation of c-Myc provide new molecular insights into the regulation of E-boxes and explain, at least in part, the increased erythroid response to 5-aza-CdR treatment.

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Control of heme synthesis during Friend cell differentiation: Role of iron and transferrin

Cited by 47 publications

References 40 publications

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Translational Regulation of Ferritin Synthesis by Iron

5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes

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