Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53.
Hepcidin is an iron-regulatory protein that is upregulated in response to increased iron or inflammatory stimuli. Hepcidin reduces serum iron and induces iron sequestration in the reticuloendothelial macrophages - the hallmark of anaemia of inflammation. Iron deprivation is used as a defense mechanism against infection, and it also has a beneficial effect on the control of cancer. The tumour-suppressor p53 transcriptionally regulates genes involved in growth arrest, apoptosis and DNA repair, and perturbation of p53 pathways is a hallmark of the majority of human cancers. This study inspected a role of p53 in the transcriptional regulation of hepcidin. Based on preliminary bioinformatics analysis, we identified a putative p53 response-element (p53RE) contained in the hepcidin gene (HAMP) promoter. Chromatin immunoprecipitation (ChIP), reporter assays and a temperature sensitive p53 cell-line system were used to demonstrate p53 binding and activation of the hepcidin promoter. p53 bound to hepcidin p53RE in vivo, andthis p53RE could confer p53-dependent transcriptional activation. Activation of p53 increased hepcidin expression, while silencing of p53 resulted in decreased hepcidin expression in human hepatoma cells. Taken together, these results define HAMP as a novel transcriptional target of p53. We hypothesise that hepcidin upregulation by p53 is part of a defence mechanism against cancer, through iron deprivation. Hepcidin induction by p53 might be involved in the pathogenesis of anaemia accompanying cancer.
Weizer-Stern
Orly
O
Cancer Research Centre and Lily and Edmond Safra Children's Hospital, Sheba Medical Centre and Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
Adamsky
Konstantin
K
Margalit
Ofer
O
Ashur-Fabian
Osnat
O
Givol
David
D
Amariglio
Ninette
N
Rechavi
Gideon
G
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D064451:Hepcidins; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D009154:Mutation; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D015850:Interleukin-6; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D007501:Iron