RRC ID 40057
Author Funauchi Y, Tanikawa C, Yi Lo PH, Mori J, Daigo Y, Takano A, Miyagi Y, Okawa A, Nakamura Y, Matsuda K.
Title Regulation of iron homeostasis by the p53-ISCU pathway.
Journal Sci Rep
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.
Volume 5
Pages 16497
Published 2015-11-12
DOI 10.1038/srep16497
PII srep16497
PMID 26560363
PMC PMC4642350
MeSH 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 Homeostasis* Humans Intracellular Space / metabolism Iron / metabolism* Iron Regulatory Protein 1 / genetics Iron Regulatory Protein 1 / metabolism Iron-Sulfur Proteins / genetics Iron-Sulfur Proteins / metabolism* Liver Neoplasms / genetics Liver Neoplasms / metabolism Mice Mice, Knockout Models, Biological Oxidoreductases Protein Binding RNA Isoforms Signal Transduction* Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism*
IF 3.998
Times Cited 25
DNA material pGL3/hISCU_p53 BR (RDB14212)