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

The expression of thyroglobulin and other thyroid-specific markers depends upon the activation of protein kinase A (PKA) by cyclic AMP. A rat thyroid cell line dedifferentiates when transformed with Ki-ras oncogene. The decrease in thyroglobulin gene expression parallels a reduction in the level of PKA nuclear catalytic subunit. We find that the activity of cAMP-responsive elements and thyroglobulin promoters is down-regulated in Ras-transformed cells. Transcription of a third cAMP-regulated gene, H-ferritin, is similarly reduced. cAMP-responsive element and H-ferritin expression were stimulated when intracellular cAMP levels were increased. Reactivation of the thyroglobulin promoter required depletion of PKC in addition to increased cAMP. We also find that v-Ras activation leads to a significant increase in membrane-bound PKC. These data support the idea that v-Ras via PKC inhibits the transmission of cAMP-PKA signals to the nucleus. We suggest that the thyroglobulin promoter is more sensitive than other cAMP-dependent promoters to reduced nuclear levels of PKA catalytic subunit.
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PMID:Ki-ras oncogene interferes with the expression of cyclic AMP-dependent promoters. 771 89

Humic acid (HA), a potential toxin that has penetrated the drinking well water of blackfoot disease-endemic areas in Taiwan, has been implicated as an etiological factor of this disease. In this study, we investigated the effects of HA on the generation of reactive oxygen species (ROS) in cultured human umbilical vein endothelial cells (HUVECs). The generation of ROS was monitored by flow cytometry. Pretreatment of HUVECs with HA induced reactive oxygen species in a dose- and time-dependent manner. Xanthine oxidase inhibitor (Allopurinol), NADPH oxidase inhibitor (diphenylene iodomium) and calcium chelator (BAPTA) could not reduce the generation of ROS. Protein kinase C inhibitor (H7) could reduce the generation of ROS slightly, but the intracellular antioxidant glutathione monoethyl ester and the iron chelator desferrioxamine (DFO) could inhibit the generation of ROS completely. HA also enhanced the expression of ferritin and induced intracellular chelatable iron; however, HA reduced the expression of transferrin receptor. Pretreatment with DFO inhibited HA-mediated increases of ferritin synthesis and intracellular chelatable iron, but caused recovery of the inhibitory effect on transferrin receptor. Cotreatment with iron and HA induced more ROS and intracellular chelatable iron than iron or HA treatment alone. Furthermore, HA enhanced the accumulation of iron in endothelial cells. These data demonstrate that HA can increase the generation of ROS through enhancing the accumulation of intracellular iron. Taken together, our findings suggest that iron mediates HA-associated oxidative stress in endothelial cells, which may be a possible mechanism leading to atherothrombotic vascular injury observed for patients with blackfoot disease.
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PMID:Induction of oxidative stress by humic acid through increasing intracellular iron: a possible mechanism leading to atherothrombotic vascular disorder in blackfoot disease. 1135 46

Atrial natriuretic peptide (ANP)-preconditioned livers are protected from ischemia-reperfusion injury. ANP-treated organs show increased expression of heme oxygenase (HO)-1. Because HO-1 liberates bound iron, the aim of our study was to determine whether ANP affects iron regulatory protein (IRP) activity and, thus, the levels of ferritin. Rat livers were perfused with Krebs-Henseleit buffer [+/-ANP, 8-bromo-cGMP (8-Br-cGMP), and tin protoporphyrin, 20 min], stored in University of Wisconsin solution (4 degrees C, 24 h), and reperfused (120 min). IRP activity was assessed by gel-shift assays, and ferritin, IRP phosphorylation, and PKC localization were assessed by Western blot. Control livers displayed decreased IRP activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion. ANP-pretreated livers showed reduced IRP activity, an effect mimicked by 8-Br-cGMP. Ferritin levels were increased in ANP-pretreated organs. Simultaneous perfusion of livers with ANP and tin protoporphyrin did not reduce ANP-induced action, arguing against a role for HO-1 in changes in IRP activity. ANP and 8-Br-cGMP decreased membrane localization of PKC-alpha and PKC-epsilon, but this modulation of PKC seems unrelated to inhibition of IRP binding. This work shows the cGMP-mediated attenuation of IRP binding activity by ANP, which results in increased hepatic ferritin levels. This change in IRPs is independent of ANP-induced HO-1 and reduced PKC activation.
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PMID:ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction. 1508 80

A variety of hematopoietic factors including granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin 3 (IL-3) and thrombopoietin (TPO) induce a rapid increase of intracellular reactive oxygen species (ROS). ROS induces the activation of many signaling molecules, including Shc, Lck, syk, PKC, MAPK, STAT3, through inhibition of protein phosphatase. Each growth factor has a specific cell-surface receptor, which activates both unique and shared signal transduction pathways. The processes of signal transduction linking cell-surface receptor to the formation of intracellular ROS have not been elucidated fully. Ferritins are composed of two subunit types, H and L, and made of 24 subunits that sequester up to 4500 atoms of iron. When the stored iron atoms are released from H-ferritin, through iron-catalyzed reaction, they have the capacity to promote the formation of ROS. Here, the interaction of G-CSFR and H-ferritin was confirmed by yeast two-hybrid screen, mammalian two-hybrid assays, glutathione-S-transferase (GST) pull-down experiments and immunoprecipitation studies in vitro and in vivo. Additional immunofluorescence assay showed that the two proteins colocalized along the plasma membrane and partly in the cytoplasm. The binding site for H-ferritin was demonstrated to locate to the box3 motif on the C-terminal region of granulocyte colony-stimulating factor receptor (G-CSFR). Furthermore, we found the interaction of full-length G-CSFR with H-ferritin was dissociated at 30 minutes after G-CSF induction and then began to assemble at 45 minutes. The labile iron pool (LIP) is a pool of redox-active iron complexes, which is regulated tightly by the expression of H-ferritin. Experiments showed that the level of LIP increased significantly at 30 minutes after G-CSF stimulation and intracellular ROS formation changed in a pattern similar to LIP response to G-CSF in bone-marrow hematopoietic cells. G-CSF-induced changes in the level of LIP and ROS formation could be blocked by pretreatment with iron chelators that repressed the expression of H-ferritin. In addition, the phosphorylation of STAT3 induced by G-CSF was decreased in iron chelator-treated hematopoietic cells. These data suggested that LIP may be released from the dissociated H-ferritin, and then induce intracellular ROS formation in the bone-marrow hematopoietic cells. ROS, acting as a second messenger, might take part in G-CSF receptor signal transduction. So, here, a new G-CSFR-H-ferritin-LIP-ROS pathway is proposed for regulation of intracellular ROS formation in bone-marrow hematopoietic cells.
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PMID:Regulation of LIP level and ROS formation through interaction of H-ferritin with G-CSF receptor. 1512 26

The Nrf2/anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants, including haem oxygenase-1 (HO-1). Various kinases have been implicated in the pathways leading to Nrf2 activation. Here, we investigated the effect of epigallocatechin (EGC) on ARE-mediated gene expression in human monocytic cells. EGC time and dose dependently increased HO-1 mRNA and protein expression but had minimal effect on expression of other ARE-regulated genes, including NAD(P)H:quinone oxidoreductase 1, glutathione cysteine ligase and ferritin. siRNA knock down of Nrf2 significantly inhibited EGC-induced HO-1 expression. Furthermore, inhibition of PKC by Ro-31-8220 dose dependently decreased EGC-induced HO-1 mRNA expression, whereas MAP kinase and phosphatidylinositol-3-kinase pathway inhibitors had no significant effect. EGC stimulated phosphorylation of PKCalphabeta and delta in THP-1 cells. PKCdelta inhibition significantly decreased EGC-induced HO-1 mRNA expression, whereas PKCalpha- and beta-specific inhibitors had no significant effect. These results demonstrate for the first time that EGC-induced HO-1 expression occurs via PKCdelta and Nrf2.
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PMID:Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cdelta and Nrf2. 1858 7

Ferritin is an iron-sequestering protein that is generally cytoplasmic; however, our previous studies have shown that in avian corneal epithelial (CE) cells ferritin is nuclear. We have also observed that this nuclear localization involves a tissue-specific nuclear transporter that we have termed ferritoid, and that nuclear ferritin protects DNA from oxidative damage. Recently we have determined that ferritoid functions not only as a nuclear transporter, but also, within the nucleus, it remains associated with ferritin as a heteropolymeric complex. This ferritoid-ferritin complex has unique properties such as being half the size of a typical ferritin molecule and showing preferential binding to DNA. It is likely that the association between ferritoid and ferritin is involved both in the nuclear transport of ferritin and in determining certain of the properties of the complex; therefore, we have been examining the mechanisms involved in regulating the association of these two components. As the ferritoid sequence contains six putative phosphorylation sites, we have examined here whether phosphorylation is one such mechanism. We have determined that ferritoid in the nuclear ferritoid-ferritin complexes is phosphorylated, and that inhibition of this phosphorylation, using inhibitors of PKC, prevents its interaction with ferritin. Furthermore, in an experimental model system in which the nuclear transport of ferritin normally occurs (i.e., the co-transfection of COS-1 cells with full length constructs for ferritin and ferritoid), when phosphorylation sites in ferritoid are mutated, the interaction between ferritoid and ferritin is inhibited, as is the nuclear transport of ferritin.
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PMID:Phosphorylation regulates the ferritoid-ferritin interaction and nuclear transport. 1936 Aug 8

CNC proteins consist of Bach1, Bach2 and 4 homologous transcription factors: Nrf1, Nrf2, Nrf3 and p45NF-E2. Transcription factors belonging to this group of proteins play a crucial role in protection of cells against oxidative stress. Under physiological conditions, they remain in the cytoplasm in the inactive form or are degraded. However, in oxidative stress conditions, they are translocated to the nucleus, and bind to DNA in the ARE sequence. Consequently, there is transcription of genes encoding cytoprotective proteins, such as phase II enzymes, or low molecular weight antioxidant proteins (i.e., thioredoxin, ferritin, metallothionein) responsible for protecting cells from reactive oxygen species (ROS) action. The activity of transcriptional proteins depends directly on the redox state of the cell. ROS as second messenger signals, control inhibitors of cytoplasmic CNC proteins or potentiate the activity of kinases (MAPK, PKC, PI3K, PERK), leading to phosphorylation of transcription factors. This is conducive to translocation of these molecules into the nucleus and to formation of complexes that initiate the gene expression. Disorders of regulation of the activity of transcription factors belonging to the CNC proteins caused by gene mutations, epigenetic modifications or increased activity of p62, p21, or k-Ras, B-Raf and c-Myc oncogenes, induce changes in the level of ARE-dependent gene expression, which can lead even to the development of carcinogenesis. On the other hand, Nrf transcription factors, inducing the expression of antioxidants and enzymes responsible for the detoxification of xenobiotics, can be considered as a potential target of the action of chemopreventive factors in anticancer therapy.
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PMID:[CNC proteins in physiology and pathology]. 2620 89