RGD Reference Report - Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis.

Authors: Dongiovanni, P  Fracanzani, AL  Cairo, G  Megazzini, CP  Gatti, S  Rametta, R  Fargion, S  Valenti, L 
Citation: Dongiovanni P, etal., Am J Pathol. 2010 Feb;176(2):1006-17. Epub 2009 Dec 17.
RGD ID: 2317357
Pubmed: PMID:20019189   (View Abstract at PubMed)
PMCID: PMC2808103   (View Article at PubMed Central)
DOI: DOI:10.2353/ajpath.2010.090249   (Journal Full-text)

Iron overload is a risk factor for hepatocarcinoma, but the pathways involved are poorly characterized. Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53. Regulation of MDM2 by iron status was observed at protein levels in mouse hepatocytes and rat liver, and was associated with specular changes in p53 expression. Iron dependent regulation of MDM2/p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis. Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. Furthermore, nutlin enhanced the antiproliferative activity of deferoxamine in HepG2 hepatoblastoma cells. The MDM2 -309T > G promoter polymorphism, determining increased MDM2 and lower p53 activity, was associated with higher risk of hepatocarcinoma in cirrhotic patients with hemochromatosis, and with HFE mutations in patients with hepatocarcinoma without hemochromatosis, suggesting an interaction between MDM2 and iron in the pathogenesis of hepatocarcinoma. In conclusion, iron status influences p53 activity and antioxidant response by modulating MDM2 expression. MDM2 inhibitors may enhance the antiproliferative activity of iron chelators.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hepatocellular carcinoma  IAGP 2317357associated with Liver Cirrhosis and DNA:missense mutation:cds:p.C282Y (human)RGD 
hepatocellular carcinoma  ISOHFE (Homo sapiens)2317357; 2317357associated with Liver Cirrhosis and DNA:missense mutation:cds:p.C282Y (human)RGD 
hepatocellular carcinoma susceptibilityIAGP 2317357DNA:transversion:promoter:g.-309T>G (human)RGD 
hepatocellular carcinoma susceptibilityISOMDM2 (Homo sapiens)2317357; 2317357DNA:transversion:promoter:g.-309T>G (human)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to iron ion  IEP 2317357 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Abnormal liver sonography  IAGP 2317357associated with Liver Cirrhosis and DNA:missense mutation:cds:p.C282YRGD 
Objects Annotated

Genes (Rattus norvegicus)
Hfe  (homeostatic iron regulator)
Mdm2  (MDM2 proto-oncogene)

Genes (Mus musculus)
Hfe  (homeostatic iron regulator)
Mdm2  (transformed mouse 3T3 cell double minute 2)

Genes (Homo sapiens)
HFE  (homeostatic iron regulator)
MDM2  (MDM2 proto-oncogene)


Additional Information