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Regulation of iron homeostasis by the p53-ISCU pathway.
- Source :
-
Scientific reports [Sci Rep] 2015 Nov 12; Vol. 5, pp. 16497. Date of Electronic Publication: 2015 Nov 12. - Publication Year :
- 2015
-
Abstract
- Accumulation of iron in tissues increases the risk of cancer, but iron regulatory mechanisms in cancer tissues are largely unknown. Here, we report that p53 regulates iron metabolism through the transcriptional regulation of ISCU (iron-sulfur cluster assembly enzyme), which encodes a scaffold protein that plays a critical role in Fe-S cluster biogenesis. p53 activation induced ISCU expression through binding to an intronic p53-binding site. Knockdown of ISCU enhanced the binding of iron regulatory protein 1 (IRP1), a cytosolic Fe-S protein, to an iron-responsive element in the 5' UTR of ferritin heavy polypeptide 1 (FTH1) mRNA and subsequently reduced the translation of FTH1, a major iron storage protein. In addition, in response to DNA damage, p53 induced FTH1 and suppressed transferrin receptor, which regulates iron entry into cells. HCT116 p53(+/+) cells were resistant to iron accumulation, but HCT116 p53(-/-) cells accumulated intracellular iron after DNA damage. Moreover, excess dietary iron caused significant elevation of serum iron levels in p53(-/-) mice. ISCU expression was decreased in the majority of human liver cancer tissues, and its reduced expression was significantly associated with p53 mutation. Our finding revealed a novel role of the p53-ISCU pathway in the maintenance of iron homeostasis in hepatocellular carcinogenesis.
- Subjects :
- Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Cell Line, Tumor
DNA Damage
Ferritins genetics
Ferritins metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Intracellular Space metabolism
Iron Regulatory Protein 1 genetics
Iron Regulatory Protein 1 metabolism
Iron-Sulfur Proteins genetics
Liver Neoplasms genetics
Liver Neoplasms metabolism
Mice
Mice, Knockout
Models, Biological
Oxidoreductases
Protein Binding
RNA Isoforms
Tumor Suppressor Protein p53 genetics
Homeostasis
Iron metabolism
Iron-Sulfur Proteins metabolism
Signal Transduction
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 26560363
- Full Text :
- https://doi.org/10.1038/srep16497