Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53

• Published in: British journal of haematology Vol. 138; no. 2; pp. 253 - 262
• Main Authors: Weizer‐Stern, Orly, Adamsky, Konstantin, Margalit, Ofer, Ashur‐Fabian, Osnat, Givol, David, Amariglio, Ninette, Rechavi, Gideon
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2007; Blackwell
• Subjects: anaemia; Anemias. Hemoglobinopathies; Anti-Bacterial Agents; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Biological and medical sciences; cancer; Cell Line, Tumor; Chromatin Immunoprecipitation - methods; Diseases of red blood cells; Gene Expression Regulation, Neoplastic - genetics; Hematologic and hematopoietic diseases; hepcidin; Hepcidins; Humans; inflammation; Interleukin-6 - genetics; iron; Iron - metabolism; Medical sciences; Mutation; p53; Response Elements - genetics; RNA Interference - physiology; RNA, Small Interfering - genetics; Transcription, Genetic - genetics; Tumor Suppressor Protein p53 - genetics; anaemia; Hematology; Anemia; Hemopathy; Iron; Inflammation; Regulator; Malignant tumor; Metabolism; p53; TP53 Gene; Hepcidin; Tumor suppressor gene; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2007.06638.x

Summary 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.