Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several metal ions that are carcinogenic affect cellular iron homeostasis by competing with iron transporters or iron-regulated enzymes. Some metal ions can mimic a hypoxia response in cells under normal oxygen tension, and induce expression of HIF-1alpha-regulated genes. This study investigated whether 12 metal ions altered iron homeostasis in human lung carcinoma A549 cells as measured by an activation of IRP-1 and ferritin level. We also studied hypoxia signaling by measuring HIF-1alpha protein levels, hypoxia response element (HRE)-driven luciferase reporter activity, and Cap43 protein level (an HIF-1alpha responsive gene). Our results show the following: (i) Ni(II), Co(II), V(V), Mn(II), and to a lesser extent As(III) and Cu(II) activated the binding of IRP-1 to IRE after 24 h, while the other metal ions had no effect; (ii) 10 of 12 metal ions induced HIF-1alpha protein but to strikingly different degrees. Two of these metal ions, Al(III) and Cd(II), did not induce HIF-1alpha protein; however, as indicated below, only Ni(II), Co (II), and to lesser extent Mn(II) and V(V) activated HIF-1alpha-dependent transcription. The combined effects of both [Ni(II) + As(III)] and [Ni(II) + Cr(VI)] on HIF-1alpha protein were synergistic; (iii) Addition of Fe(II) with Ni(II), Co(II), and Cr(VI) attenuated the induction of HIF-1alpha after 4 h treatment; (iv) Ni(II), Co(II), and Mn(II) significantly decrease ferritin level after 24 h exposure; (v) Ni(II), Co(II), V(V), and Mn(II) activated HRE reporter gene after 20 h treatment; (vi) Ni(II), Co(II), V(V), and Mn(II) increased the HIF-1-dependent Cap43 protein level after 24 h treatment. In conclusion, only Ni (II), Co (II), and to a lesser extent Mn(II) and V(V) significantly stabilized HIF-1alpha protein, activated IRP, decreased the levels of ferritin, induced the transcription of HIF-dependent reporter, and increased the expression of Cap43 protein levels (HIF-dependent gene). The mechanism for the significant stabilization and elevation of HIF-1alpha protein which drives these other parameters was previously shown by us and others to involve a loss of cellular Fe as well as inhibition of HIF-1alpha-dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF-1alpha. Even though there were small effects of some of the other metals on IRP and HIF-1alpha, downstream effects of HIF-1alpha activation and therefore robust hypoxia signaling were only observed with Ni(II), Co(II), and to much lesser extents with Mn(II) and V(V) in human A549 lung cells. It is of interest that the metal ions that were most effective in activating hypoxia signaling were the ones that were poor inducers of metallothionein protein and also decreased Ferritin levels, since both of these proteins can bind metal ions and protect the cell against toxicity in human lung cells. It is important to study effects of these metals in human lung cells since this represents a major route of human environmental and occupational exposure to these metal ions.
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PMID:Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes. 1638 71

NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting.
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PMID:Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. 2643 93

Iron (Fe) is an essential nutrient for all living organisms but can lead to cytotoxicity when present in excess. Fe toxicity often occurs in rice grown in submerged paddy fields with low pH, leading dramatical increases in ferrous ion concentration, disrupting cell homeostasis and impairing growth and yield. However, the underlying molecular mechanisms of Fe toxicity response and tolerance in plants are not well characterized yet. Microarray and genome-wide association analyses have shown that rice employs four defense systems to regulate Fe homeostasis under Fe excess. In defense 1, Fe excess tolerance is implemented by Fe exclusion as a result of suppression of genes involved in Fe uptake and translocation such as OsIRT1, OsYSL2, OsTOM1, OsYSL15, OsNRAMP1, OsNAS1, OsNAS2, OsNAAT1, OsDMAS1, and OsIRO2. The Fe-binding ubiquitin ligase, HRZ, is a key regulator that represses Fe uptake genes in response to Fe excess in rice. In defense 2, rice retains Fe in the root system rather than transporting it to shoots. In defense 3, rice compartmentalizes Fe in the shoot. In defense 2 and 3, the vacuolar Fe transporter OsVIT2, Fe storage protein ferritin, and the nicotinamine synthase OsNAS3 mediate the isolation or detoxification of excess Fe. In defense 4, rice detoxifies the ROS produced within the plant body in response to excess Fe. Some OsWRKY transcription factors, S-nitrosoglutathione-reductase variants, p450-family proteins, and OsNAC4, 5, and 6 are implicated in defense 4. These knowledge will facilitate the breeding of tolerant crops with increased productivity in low-pH, Fe-excess soils.
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PMID:How Does Rice Defend Against Excess Iron?: Physiological and Molecular Mechanisms. 3284 82