Document Detail


Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis.
MedLine Citation:
PMID:  17938254     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. However, the mechanisms regulating the 2 HJV isoforms remain unclear. Here we show that s-HJV originates from a furin cleavage at position 332-335. s-HJV is reduced in the cleavage mutant R335Q as well as in cells treated with a furin inhibitor, and increased in cells overexpressing exogenous furin, but not in cells overexpressing an inactive furin variant. Furin is up-regulated by iron deficiency and hypoxia in association with the stabilization of HIF-1alpha. Increased s-HJV in response to HIF-1alpha occurs during differentiation of murine muscle cells expressing endogenous Hjv. Our data are relevant to the mechanisms that relate iron metabolism to the hypoxic response. The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver.
Authors:
Laura Silvestri; Alessia Pagani; Clara Camaschella
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-15
Journal Detail:
Title:  Blood     Volume:  111     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-09     Completed Date:  2008-03-11     Revised Date:  2012-02-24    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  924-31     Citation Subset:  AIM; IM    
Affiliation:
Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele, Milan, Italy.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Animals
Antimicrobial Cationic Peptides / biosynthesis,  genetics
Bone Morphogenetic Proteins / genetics,  metabolism
Cell Differentiation / physiology
Cell Hypoxia / physiology
Down-Regulation / physiology
Furin / genetics,  metabolism*
GPI-Linked Proteins
HeLa Cells
Homeostasis / physiology*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism
Iron / deficiency,  metabolism*
Iron Overload / genetics,  microbiology*
Liver / cytology,  metabolism*
Membrane Proteins / genetics,  metabolism*
Mice
Muscle Cells / cytology,  metabolism
Muscle, Skeletal / cytology,  metabolism
Mutation, Missense
Organ Specificity / physiology
Oxygen / metabolism
Protein Isoforms / genetics,  metabolism
Signal Transduction / physiology
Grant Support
ID/Acronym/Agency:
GTF05007//Telethon
Chemical
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/Bone Morphogenetic Proteins; 0/GPI-Linked Proteins; 0/HFE2 protein, human; 0/HIF1A protein, human; 0/Hfe2 protein, mouse; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Membrane Proteins; 0/Protein Isoforms; 0/hepcidin; 7439-89-6/Iron; 7782-44-7/Oxygen; EC 3.4.21.75/FURIN protein, human; EC 3.4.21.75/Furin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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