Regulation of Expression of Ferritin H‐chain and Transferrin Receptor by Protoporphyrin IX

Coccia, Eliana M.; Perrotti, Edvige; Stellacci, Emilia; Orsatti, Roberto; Russo, Nicoletta Del; Marziali, Giovanna; Testa, Ugo; Battistini, Angela

doi:10.1111/j.1432-1033.1997.00764.x

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…Effect of HO Expression on Ferritin Protein Levels-In many model systems, iron (34,35) and increased HO activity (35,36) have been shown to regulate ferritin. It is thought that increased ferritin content serves to sequester redox active iron, thereby enhancing protection against oxidative stress (7).…”

Section: Effect Of Overexpression Of Ho-1 In O 2 R95 Cells-othersmentioning

confidence: 99%

Heme Oxygenase-mediated Resistance to Oxygen Toxicity in Hamster Fibroblasts

Dennery

Sridhar

Lee

et al. 1997

Journal of Biological Chemistry

129

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The role of heme oxygenase (HO)-1 was evaluated in the oxygen-resistant hamster fibroblast cell line, O 2 R95, which moderately overexpress HO when compared with the parental cell line, HA-1. To suppress HO-1 expression, O 2 R95 were transfected with HO-1 antisense oligonucleotide or treated with tin-mesoporphyrin (SnMP). To increase HO-1 expression, cells were transfected with HO-1 cDNA in a pRC/cytomegalovirus (CMV) vector. All cells were challenged with a 48-h exposure to 95% O 2 (hyperoxia). When HO activity was suppressed, O 2 R95 cells had significantly decreased cell viability, increased susceptibility to lipid peroxidation, and increased protein oxidation in hyperoxia. In contrast, further overexpression of HO-1 did not improve resistance to oxygen toxicity. Antisense-transfected cells and SnMP-treated cells with lowered HO activity showed increased levels of cellular heme compared with controls. In the HO-1 cDNA-transfected O 2 R95 cells, cellular heme was lowered compared with controls; however, cellular redox active iron levels were increased. We conclude that HO mediates cytoprotection to oxygen toxicity within a narrow range of expression. We speculate that this protective effect may be mediated in part through increased metabolism of the pro-oxidant heme but that higher levels of HO activity obviate protection by increased redox active iron release.Heme oxygenase (HO-1), 1 the rate-limiting enzyme in the conversion of heme to bilirubin, is known to be induced by various oxidant stresses. However, it is not clear whether HO serves in protection against hyperoxia and, if so, by which mechanisms. HO-1 antisense transfection experiments have shown that higher HO-1 protein levels were associated with protection against UVA radiation (1). Furthermore, transfection of coronary vessel endothelial cells with an overexpression vector containing HO-1 cDNA resulted in resistance against hemoglobin-induced injury (2). We have previously shown that HA-1 hamster fibroblasts made stably resistant to oxygen toxicity (O 2 R95) had 1.8-fold higher HO activity (3), suggesting that moderate increases in HO activity may be beneficial in resistance to oxygen toxicity. However, O 2 R95 cells have increases in other antioxidants that may also contribute to their resistance to oxygen toxicity (4), and no direct evidence currently exists linking HO to resistance to oxygen toxicity.Investigators have hypothesized that HO may serve a role in protection against oxidative injury by forming the antioxidant molecules biliverdin and bilirubin (5, 6). Additionally, induction of ferritin with enhanced HO activity has been observed (1). This could lead to sequestration of redox active iron, thereby conferring protection against oxidative stress (7). Another possible antioxidant mechanism of HO could involve the destruction of heme itself. Heme and hemoproteins have been shown by several investigators to be instrumental in exacerbating oxidative injury (8, 9). This has lead to the hypothesis that reduction of the cellular heme pool by ...

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Section: Effect Of Overexpression Of Ho-1 In O 2 R95 Cells-othersmentioning

confidence: 99%

Heme Oxygenase-mediated Resistance to Oxygen Toxicity in Hamster Fibroblasts

Dennery

Sridhar

Lee

et al. 1997

Journal of Biological Chemistry

129

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“…Since hemin is comprised of ferric iron enclosed in protoporphyrin IX ring, PrP C could facilitate transport of iron released from hemin across the endosomal membrane, promote protoporphyrin IX-mediated upregulation of α-globin and β-globin synthesis [55, 56], or increase de novo incorporation of hemin in newly synthesized Hb [57]. To distinguish between these possibilities, K562 cells expressing vector, PrP C , or PrP Δ51-89 were exposed to hemin or ferrous ammonium citrate (FAC) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Re-probing for ferritin, Tf, and TfR revealed downregulation of ferritin and upregulation of TfR in PP IX-treated cells, indicating depletion of cellular iron stores by this treatment due to stimulation of Hb synthesis (Fig. 6A, lanes 1–3 versus 4–6) [55, 58]. …”

Section: Resultsmentioning

confidence: 99%

Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease

Tripathi¹,

Singh²

2016

JAD

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Hemin is known to induce endocytosis of prion-protein (PrPC) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrPSc) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrPC interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrPC. Interestingly, PrPC is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrPC on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrPC interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrPC. A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP+/+) relative to PrP-knock-out (PrP−/−) samples. Furthermore, red blood cells and brain tissue from PrP−/− mice show significantly less α-globin relative to PrP+/+ controls, indicating a positive effect of PrPC on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrPC that is likely to impact the therapeutic management of CH and sCJD.

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“…It seems likely that both are involved, and that the relative importance of each may be determined by variables such as cell type (33) and cell physiological state (25,26). However, the fact that the re-repression after iron treatment requires new protein synthesis is consistent with the degradation pathway being operational in the cells employed (26).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Heme in the Degradation of Iron-regulatory Protein 2

Goessling¹,

Mascotti²,

Thach³

1998

Journal of Biological Chemistry

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Iron-regulatory proteins (IRPs) recognize and bind to specific RNA structures called iron-responsive elements. Mediation of these binding interactions by iron and iron-containing compounds regulates several posttranscriptional events relevant to iron metabolism. There are two known IRPs, IRP1 and IRP2, both of which can respond to iron fluxes in the cell. There is ample evidence that IRP1 is converted by iron to cytoplasmic aconitase in vivo. It has also been shown that, under certain conditions, a significant fraction of IRP1 is degraded in cells exposed to iron or heme. Studies have shown that the degradation of IRP1 that is induced by iron can be inhibited by either desferrioxamine mesylate (an iron chelator) or succinyl acetone (an inhibitor of heme synthesis), whereas the degradation induced by heme cannot. This suggests that heme rather than iron is responsible for this degradation.Several laboratories have shown that IRP2 is also degraded in cells treated with iron salts. We now show evidence suggesting that this IRP2 degradation may be mediated by heme. Thus, in experiments analogous to those used previously to study IRP1, we find that IRP2 is degraded in rabbit fibroblast cells exposed to heme or iron salts. However, as shown earlier with IRP1, both desferrioxamine mesylate and succinyl acetone will inhibit the degradation of IRP2 induced by iron but not that induced by heme.

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Regulation of Expression of Ferritin H‐chain and Transferrin Receptor by Protoporphyrin IX

Cited by 8 publications

References 54 publications

Heme Oxygenase-mediated Resistance to Oxygen Toxicity in Hamster Fibroblasts

Heme Oxygenase-mediated Resistance to Oxygen Toxicity in Hamster Fibroblasts

Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease

Involvement of Heme in the Degradation of Iron-regulatory Protein 2

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