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Cancer Cell ; 20(4): 524-37, 2011 Oct 18.
Article in English | MEDLINE | ID: mdl-22014577

ABSTRACT

The Krebs cycle enzyme fumarate hydratase (FH) is a human tumor suppressor whose inactivation is associated with the development of leiomyomata, renal cysts, and tumors. It has been proposed that activation of hypoxia inducible factor (HIF) by fumarate-mediated inhibition of HIF prolyl hydroxylases drives oncogenesis. Using a mouse model, we provide genetic evidence that Fh1-associated cyst formation is Hif independent, as is striking upregulation of antioxidant signaling pathways revealed by gene expression profiling. Mechanistic analysis revealed that fumarate modifies cysteine residues within the Kelch-like ECH-associated protein 1 (KEAP1), abrogating its ability to repress the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response pathway, suggesting a role for Nrf2 dysregulation in FH-associated cysts and tumors.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cytoskeletal Proteins/metabolism , Fumarate Hydratase/physiology , Fumarates/metabolism , Kidney Diseases, Cystic/metabolism , NF-E2-Related Factor 2/metabolism , Succinates/metabolism , Animals , Antioxidants/metabolism , Cell Hypoxia , Fumarate Hydratase/genetics , Fumarate Hydratase/metabolism , Gene Expression Regulation, Neoplastic , Hypoxia-Inducible Factor 1/genetics , Hypoxia-Inducible Factor 1/metabolism , Kelch-Like ECH-Associated Protein 1 , Kidney Diseases, Cystic/genetics , Mice , Procollagen-Proline Dioxygenase/metabolism , Signal Transduction
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