Regulation of iron homeostasis by the p53-ISCU pathway.
Regulation of iron homeostasis by the p53-ISCU pathway.
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DOI：
10.1038/srep16497
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发表时间：
2015-11-12
影响因子：
4.6
通讯作者：
Matsuda K
中科院分区：
文献类型：
--
作者：
Funauchi Y;Tanikawa C;Yi Lo PH;Mori J;Daigo Y;Takano A;Miyagi Y;Okawa A;Nakamura Y;Matsuda K
铁在组织中的积累会增加癌症的风险，但癌症组织中的铁调节机制在很大程度上是未知的。在这里，我们报告说，p53调节铁代谢通过转录调控ISCU（铁硫簇组装酶），它编码的支架蛋白，在铁硫簇生物合成中起着关键作用。p53激活通过结合到内含子p53结合位点诱导ISCU表达。敲低ISCU可增强铁调节蛋白1（IRP 1）与铁蛋白重链多肽1（FTH 1）mRNA 5′非翻译区中的铁响应元件的结合，从而减少主要铁储存蛋白FTH 1的翻译。此外，作为对DNA损伤的响应，p53诱导FTH 1并抑制转铁蛋白受体，该受体调节铁进入细胞。HCT 116 p53+/+细胞对铁积累有抵抗力，但HCT 116 p53−/−细胞在DNA损伤后积累细胞内铁。此外，过量的膳食铁会导致p53-/-小鼠的血清铁水平显着升高。ISCU在大多数人肝癌组织中表达降低，且其表达降低与p53突变显著相关。我们的发现揭示了p53-ISCU通路在肝细胞癌发生过程中维持铁稳态的新作用。
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.