Ferritin binds and activates p53 under oxidative stress

National Research Laboratory for Metabolic Checkpoint, Department of Biomedical Sciences & Biochemistry, Seoul National University College of Medicine, Seoul, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/2009; 389(3):399-404. DOI: 10.1016/j.bbrc.2009.08.125
Source: PubMed


Ferritin, an iron storage protein, plays an essential role in iron homeostasis and a wide range of physiologic processes. Ferritin alleviates oxidative stress by regulating cellular labile iron concentration. The tumor suppressor p53 is induced upon iron depletion, and controls reactive oxygen species level. Although some functional connections between ferritin and p53 were implied in several reports, the direct links between ferritin and p53 has not yet been investigated. Here we report that ferritin physically interacts with p53 upon oxidative stress. Ferritin increases p53 protein level and p53 transcriptional activity in ferroxidase activity independent manner. Ferritin knocked down cells show retarded induction of p53 target genes upon oxidative stress. These findings suggest that ferritin cooperates with p53 to cope with oxidative stress.

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    • "The concentration of Ferritin increases in response to stresses including anoxia, pathogenesis and carcinogenesis [60]. For instance, it has also been reported that Ferritin binds and activates p53 under oxidative stress [61] and the overexpression of H-ferritin (Ferritin heavy subunit) promotes radiation-induced leukemia/lymphoma in mice [62]. Interestingly, both frh3 and slc40a1 were identified to be up-regulated by arsenic in both zebrafish and medaka in the present study (Figure 4). "
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    ABSTRACT: Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down-regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT-qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure.
    PLoS ONE 07/2013; 8(7):e68737. DOI:10.1371/journal.pone.0068737 · 3.23 Impact Factor
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    • "Speculative mechanisms (seen in other cell types) stabilize p53 protein levels under oxidative stress [129]. The activation of p53 can lead to a variety of cellular responses, including apoptosis. "
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    ABSTRACT: Human immunodeficiency virus 1 (HIV-1) and its associated proteins can have a profound impact on the central nervous system. Co-morbid abuse of opiates, such as morphine and heroin, is often associated with rapid disease progression and greater neurological dysfunction. The mechanisms by which HIV proteins and opiates cause neuronal damage on their own and together are unclear. The emergence of ferritin heavy chain (FHC) as a negative regulator of the chemokine receptor CXCR4, a co-receptor for HIV, may prove to be important in elucidating the interaction between HIV proteins and opiates. This review summarizes our current knowledge of central nervous system damage inflicted by HIV and opiates, as well as the regulation of CXCR4 by opiate-induced changes in FHC protein levels. We propose that HIV proteins and opiates exhibit an additive or synergistic effect on FHC/CXCR4, thereby decreasing neuronal signaling and function.
    Current HIV research 05/2012; 10(5):453-62. DOI:10.2174/157016212802138751 · 1.76 Impact Factor
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    • "H-subunit rich ferritins have also been found to take part in the apoptotic events not involving iron or its ferroxidase activity. Upon oxidative stress, H-subuint rich ferritins increase p53 protein levels and p53 transcriptional activity in a ferroxidase activityindependent manner (Lee et al., 2009). The gene coding for the H-subunit of ferritin belongs to the family of p53-regulated genes. "
    Acute Phase Proteins - Regulation and Functions of Acute Phase Proteins, 10/2011; , ISBN: 978-953-307-252-4
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