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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the pathogenesis of hepatic iron toxicity, we investigated the effect of chronic dietary iron overload on the expression of several genes in rat liver. After 10 wk of iron treatment, when only minor histological features of liver damage were appreciable, the level of pro-alpha 2(I)-collagen mRNA was already higher than in control liver and increased further at 30 wk of treatment. Also, the relative amount of L ferritin subunit mRNA was enhanced early by iron load and was even more elevated at the latest time point considered, whereas neither H ferritin subunit nor transferrin mRNA levels were affected by iron treatment. In contrast, after chronic iron treatment, no variations were found in the steady-state level of mRNAs transcribed from liver-specific and preferentially expressed genes (albumin, alpha-fetoprotein, apolipoprotein A-1), growth-related genes (c-myc, c-Ha-ras and c-fos) and stress-induced genes (heat shock protein 70). These results suggest that chronic dietary iron overload in rats can specifically activate target genes in the liver (i.e., L ferritin and procollagen) in the absence of either histological signs of severe liver damage or alterations in differentiated liver functions.
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PMID:Liver gene expression during chronic dietary iron overload in rats. 169 54

Turnover of the full-length human transferrin receptor (TfR) mRNA is regulated by iron, and this regulation is mediated by the transcript's 3' untranslated region. Alterations in the sequence of the TfR mRNA regulatory region have been identified that render the mRNA unregulated by iron and intrinsically unstable. When cells expressing this unstable mRNA are treated with inhibitors of protein synthesis (cycloheximide or puromycin), the steady-state level of the encoded human TfR mRNA is increased due to a stabilization of the transcript. A similar set of observations has been made using a chimeric mRNA in which the rapid turnover determinant of the TfR mRNA is replaced by the (A+U)-rich region from the 3' untranslated region of c-fos mRNA. To distinguish between a labile protein participant in the degradation of these mRNAs and a requirement for their translation per se, we introduced a ferritin iron-responsive element into the 5' untranslated region of each of these mRNAs. The presence of the 5' iron-responsive element allowed us to use iron availability to alter the translation of the mRNAs in question without global effects on cellular protein synthesis. Although specific translation of these mRNAs could be inhibited by iron chelation to a degree comparable to that seen with cycloheximide (approximately 95% inhibition), no effects on mRNA turnover were observed. These data support a model in which a trans-acting labile protein is necessary for the turnover of these mRNAs rather than there being a requirement for the translation of the mRNAs themselves.
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PMID:Translation and the stability of mRNAs encoding the transferrin receptor and c-fos. 190 29

The instability of oncogenic mRNA such as c-fos mRNA is controlled in cis by sequences present in both the coding and the 3' untranslated regions (3'UTR). The latter contains AU-rich elements (ARE) which, depending on the cellular context, mediate either their rapid degradation or inhibit their translation. These observations, along with the known increase of the life spans of many unstable mRNA promoted by inhibitors of protein synthesis, raise the possibility that both processes are linked. To investigate further the putative involvement of translation in both coding region and ARE-mediated rapid decay of c-fos mRNA, we designed an expression vector based on the use of the ferritin mRNA iron regulatory element (IRE). The latter structure links translation to intracellular iron concentration when inserted at the proper location within the 5'UTR. Rapid degradation of a beta-globin/c-fos 3'UTR construct was prevented by Desferrioxamine, an iron chelator, and facilitated by ferric ammonium citrate or hemin, while stability of other mRNAs not containing the IRE or the ARE were unchanged. The same conclusion was reached when the stability of a c-fos mRNA devoid of ARE was assessed in function of iron availability.
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PMID:c-fos mRNA instability determinants present within both the coding and the 3' non coding region link the degradation of this mRNA to its translation. 747 33

The different 3' noncoding AU-rich elements (ARE) that mediate the degradation of many short-lived mRNAs may function through distinct decay pathways; translation-dependent and -independent mechanisms have been proposed. To investigate the cotranslational model, we designed an expression system that exploits the properties of the ferritin iron-responsive element to shuttle chimeric mRNAs from ribonucleoproteins to polyribosomes. The iron-responsive element was introduced in the 5' untranslated regions of alpha-globin mRNAs that harbored in their 3' untranslated regions either the c-fos ARE or the granulocyte-macrophage colony-stimulating factor ARE as prototypes of the different ARE subsets. The cytoplasmic location of the transcripts was controlled by intracellular iron availability and monitored by polysomal profile analysis. We report that these two mRNA subsets behaved identically in this system. Iron deprivation by desferrioxamine treatment stabilized both transcripts by sequestering them away from polyribosomes. Sequential treatments with desferrioxamine, followed by hemin to concentrate the mRNAs in the ribonucleoprotein pool prior to translation, showed that rapid degradation occurred only upon redistribution of the transcripts to polyribosomes. Deletion of a critical cytosine in the iron-responsive element abolished targeted sequestration and restored high-level constitutive mRNA instability. These observations demonstrate that the c-fos and granulocyte-macrophage colony-stimulating factor ARE subsets mediate selective mRNA degradation through similar polysome-associated mechanisms coupled with ongoing translation.
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PMID:Rapid mRNA degradation mediated by the c-fos 3' AU-rich element and that mediated by the granulocyte-macrophage colony-stimulating factor 3' AU-rich element occur through similar polysome-associated mechanisms. 754 Jul 19

Ferritin, the major intracellular iron storage protein of eucaryotic cells, is regulated during inflammation and malignancy. We previously reported that transcription of the H subunit of ferritin (ferritin H) is negatively regulated by the adenovirus E1A oncogene in mouse NIH 3T3 fibroblasts (Y. Tsuji, E. Kwak, T. Saika, S. V. Torti, and F. M. Torti, J. Biol. Chem. 268:7270-7275, 1993). To elucidate the mechanism of transcriptional repression of the ferritin H gene by E1A, a series of deletions in the 5' flanking region of the mouse ferritin H gene were constructed, fused to the chloramphenicol acetyltransferase (CAT) gene, and transiently cotransfected into NIH 3T3 cells with an E1A expression plasmid. The results indicate that the E1A-responsive region is located approximately 4.1 kb 5' to the transcription initiation site of the ferritin H gene. Further analyses revealed that a 37-bp region, termed FER-1, is the target of E1A-mediated repression. This region also serves as an enhancer, augmenting ferritin H transcription independently of position and orientation. FER-1 was dissected into two component elements, i.e., a 22-bp dyad symmetry element and a 7-bp AP1-like sequence. Insertion of these DNA sequences into a ferritin H-CAT chimeric gene lacking an E1A-responsive region indicated that (i) the 22-bp dyad symmetry sequence by itself has no enhancer activity, (ii) the AP1-like sequence has moderate enhancer activity which is repressed by E1A, and (iii) the combination of the dyad symmetry element and the AP1-like sequence is required for maximal enhancer activity and repression by E1A. Gel retardation assays and cotransfection experiments with c-fos and c-jun expression vectors suggested that members of the Fos and Jun families bind to the AP1-like element of FER-1 and contribute to its regulation. In addition, gel retardation assays showed that E1A reduces the ability of nuclear proteins to bind to the AP1-like sequence without affecting the levels of nuclear factors that recognize the 22-bp dyad symmetry element. Taken together, these results demonstrate that FER-1 serves as both an enhancer of ferritin H transcription and a target for E1A-mediated repression.
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PMID:FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression. 765 32

In the liver, CCl4 induces cell necrosis followed by regeneration. Cell injury is caused by free radical damage and may be due, at least in part, to oxidative stress and the subsequent formation of reactive oxygen intermediates (ROIs). In a rat model of acute CCl4-induced hepatic injury, we examined the expression of genes involved in cellular response to different kinds of stress, including oxidative stress (hsp 70 family, heme oxygenase), in free radical detoxification (Mn superoxide dismutase and Cu/ Zn superoxide dismutase), in iron homeostasis (H and L ferritin subunits) and in the cell cycle (c-fos, c-jun, histone H3). As an experimental approach, we first analysed the pattern of protein synthesised by liver slices in vitro. Then we studied the mechanisms regulating the expression of different genes, by analysing both mRNA steady state levels and transcription rates. Activation of the specific heat shock transcription factor (HSF) by CCl4 was also investigated. We observed that different members of the hsp70 family (hsp70, hsc73, grp78) are activated by different kinetics and are regulated mainly at the transcriptional level. Induction of the hsp70 gene occurs rapidly and transiently and is preceded by the activation of HSF DNA-binding activity. We demonstrated an increase in the steady-state levels of mRNAs for heme oxygenase, Mn and Cu/Zn superoxide dismutases and H and L ferritin subunits. However, different kinetics and regulatory mechanisms occurred with different genes. We showed that induction of c-fos and c-jun protooncogenes is the earliest event after CCl4 administration, whereas histone H3 expression peaked at 24-48 h. The results of this study are interpreted as evidence that activation of specific stress response genes is primarily related to the defence against the rapidly occurring cell damage, but may also be related to subsequent processes of tissue inflammation and cell proliferation.
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PMID:Gene expression in liver after toxic injury: analysis of heat shock response and oxidative stress-inducible genes. 929 88

The ultraviolet A (UVA, 320-400 nm) component of sunlight has the potential to generate an oxidative stress in cells and tissue so that antioxidants (both endogenous and exogenous) strongly influence the biological effects of UVA. The expression of several genes (including heme oxygenase-1, HO-1; collagenase; the CL100 phosphatase and the nuclear oncogenes, c-fos and c-jun) is induced following physiological doses of UVA to cells and this effect can be strongly enhanced by removing intracellular glutathione or enhancing singlet oxygen lifetime. We have observed that heme is released from microsomal heme-containing proteins by UVA and other oxidants and that activation of HO-1 expression by UVA correlates with levels of heme release. UVA radiation also leads to an increase in labile iron pools (either directly or via HO-1) and eventual increases in ferritin levels. The role of heme oxygenase in protection of skin fibroblasts is probably an emergency inducible defense pathway to remove heme liberated by oxidants. The slower increase in ferritin levels is an adaptive response which serves to keep labile iron pools low and thereby reduce Fenton chemistry and oxidant-induced chain reactions involving lipid peroxidation. In keratinocytes, the primary target of UVA radiation, heme oxygenase levels are constitutively high (because of HO-2 expression). Since there is a corresponding increase in basal levels of ferritin the epidermis appears to be well protected constitutively against the oxidative stress generated by UVA.
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PMID:Redox regulation and oxidant activation of heme oxygenase-1. 1051 38