Modulation of ferritin H-chain expression in Friend erythroleukemia cells: transcriptional and translational regulation by hemin.

Coccia, Eliana M.; Profita, V; Fiorucci, G; Romeo, Giovanna; Affabris, Elisabetta; Testa, Ugo; Hentze, M W; Battistini, Angela

doi:10.1128/mcb.12.7.3015

Cited by 47 publications

(41 citation statements)

References 29 publications

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“…3C) and, with the IRE, gave equal responses to FAC or hemin (Fig. 3D), confirming earlier observations that hemin inhibits IRE͞IRP interactions (25) and that FAC and hemin both increase ferritin synthesis (24). The response to hemin of the combined MARE͞ ARE and IRE regulatory elements (Fig.…”

Section: Resultssupporting

confidence: 77%

“…When the DNA-MARE͞ARE and the mRNA-IRE were both present, hemin increased luciferase activity Ϸ9-fold (Fig. 3B), consistent with endogenous ferritin-L expression in hemin-treated Friend's leukemia cells (24) and contrasting with the 2-to 3-fold hemin or PPIX induction with the DNA-MARE͞ARE alone (Fig. 3A) and when the IRE was coupled to an inactive MARE͞ARE (Fig.…”

Section: Resultsmentioning

confidence: 62%

“…1D); equivalent responses required only 2 M SF compared to 1,600 M FAC (Fig. 1D), an 800-fold difference; only Ϸ100-200 M FAC is needed to induce ferritin protein synthesis (24). The relative insensitivity of ferritin-L transcription to FAC has also been observed in whole animal experiments (20)(21)(22).…”

Section: Resultsmentioning

confidence: 69%

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DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Hintze¹,

Theil²

2005

Proc. Natl. Acad. Sci. U.S.A.

165

147

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Ferritins, an ancient family of protein nanocages, concentrate iron in iron-oxy minerals for iron-protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert-butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE͞ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE͞ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE͞ARE or IRE alone. Regulation of ferritin-L by a MARE͞ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.antioxidant responsive element ͉ Maf recognition element ͉ oxygen ͉ iron responsive element ͉ combinatorial regulation

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 62%

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DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Hintze¹,

Theil²

2005

Proc. Natl. Acad. Sci. U.S.A.

165

147

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“…This effect is mediated, at least in some genes, by the zinc finger transcription factor HAP-1, which binds DNA in the presence of heme (61,62). The presence of DNA regulatory proteins that bind the promoter of the mammalian ferritin gene in a heme-dependent manner has also been described recently, and in this case the effect is mediated by the ubiquitous transcription factor NF-Y (47,63,64). Another example of a gene regulated at the transcriptional level by heme is the tartrate-resistant acid phosphatase.…”

Section: Cloning and Structure Of The Drosophila Alas Gene-twomentioning

confidence: 99%

Structure and Regulated Expression of the δ-Aminolevulinate Synthase Gene from Drosophila melanogaster

Mena¹,

Fernández-Moreno²,

Börnstein³

et al. 1999

Journal of Biological Chemistry

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The structure of the single copy gene encoding the putative housekeeping isoform of Drosophila melanogaster ␦-aminolevulinate synthase (ALAS) has been determined. Southern and immunoblot analyses suggest that only the housekeeping isoform of the enzyme exists in Drosophila. We have localized a critical region for promoter activity to a sequence of 121 base pairs that contains a motif that is potentially recognized by factors of the nuclear respiratory factor-1 (NRF-1)/P3A2 family, flanked by two AP4 sites. Heme inhibits the expression of the gene by blocking the interaction of putative regulatory proteins to its 5 proximal region, a mechanism different from those proposed for other hemin-regulated promoters. Northern and in situ RNA hybridization experiments show that maternal alas mRNA is stored in the egg; its steady-state level decreases rapidly during the first hours of development and increases again after gastrulation in a period where the synthesis of several mRNAs encoding metabolic enzymes is activated. In the syncytial blastoderm, the alas mRNA is ubiquitously distributed and decreases in abundance substantially through cellular blastoderm. Late in embryonic development alas shows a specific pattern of expression, with an elevated mRNA level in oenocytes, suggesting an important role of these cells in the biosynthesis of hemoproteins in Drosophila.

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“…H-subunit rich ferritins have been shown to accumulate and release iron faster than do L-subunit rich ferritins Chiancone & Stefanini, 1984;Wagstaff et al, 1982;Worwood, 1990) and it is suggested that the H-subunit rich ferritins permit more dynamic in-tracellular traffic of iron (Chiancone & Stefanini, 1984;Speyer & Fielding, 1979). L-subunit rich ferritins apparently contain more iron than those ferritins rich in H-subunits (Bomford et al, 1981;Chiancone & Stefanini, 1984) and there are indications that the L-subunit rich ferritins predominate in cell types that play a role in the storage of iron (Boyd et al, 1985;Chiancone & Stefanini, 1984;Coccia et al, 1992;Powell et al, 1975). However, increases in ferritins rich in the H-subunit have been shown to provide cells with increased resistance to H 2 O 2 toxicity (Cozzi et al, 2000).…”

Section: Isoferritins Different H-subunit/l-subunit Compositions Of Tmentioning

confidence: 99%

Ferritin and ferritin isoforms I: Structure–function relationships, synthesis, degradation and secretion

Koorts

Viljoen

2007

Archives of Physiology and Biochemistry

133

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Ferritin is the intracellular protein responsible for the sequestration, storage and release of iron. Ferritin can accumulate up to 4500 iron atoms as a ferrihydrite mineral in a protein shell and releases these iron atoms when there is an increase in the cell's need for bioavailable iron. The ferritin protein shell consists of 24 protein subunits of two types, the H-subunit and the L-subunit. These ferritin subunits perform different functions in the mineralization process of iron. The ferritin protein shell can exist as various combinations of these two subunit types, giving rise to heteropolymers or isoferritins. Isoferritins are functionally distinct and characteristic populations of isoferritins are found depending on the type of cell, the proliferation status of the cell and the presence of disease. The synthesis of ferritin is regulated both transcriptionally and translationally. Translation of ferritin subunit mRNA is increased or decreased, depending on the labile iron pool and is controlled by an ironresponsive element present in the 5'-untranslated region of the ferritin subunit mRNA. The transcription of the genes for the ferritin subunits is controlled by hormones and cytokines, which can result in a change in the pool of translatable mRNA. The levels of intracellular ferritin are determined by the balance between synthesis and degradation. Degradation of ferritin in the cytosol results in complete release of iron, while degradation in secondary lysosomes results in the formation of haemosiderin and protection against iron toxicity. The majority of ferritin is found in the cytosol. However, ferritin with slightly different properties can also be found in organelles such as nuclei and mitochondria. Most of the ferritin produced intracellularly is harnessed for the regulation of iron bioavailability; however, some of the ferritin is secreted and internalized by other cells. In addition to the regulation of iron bioavailability ferritin may contribute to the control of myelopoiesis and immunological responses.

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Modulation of ferritin H-chain expression in Friend erythroleukemia cells: transcriptional and translational regulation by hemin.

Abstract: The mechanisms that regulate the expression of the H chain of the iron storage

Cited by 47 publications

References 29 publications

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Structure and Regulated Expression of the δ-Aminolevulinate Synthase Gene from Drosophila melanogaster

Ferritin and ferritin isoforms I: Structure–function relationships, synthesis, degradation and secretion

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