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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antioxidants / metabolism
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Cell Hypoxia
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Cytoskeletal Proteins / metabolism*
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Fumarate Hydratase / genetics
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Fumarate Hydratase / metabolism
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Fumarate Hydratase / physiology*
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Fumarates / metabolism*
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Gene Expression Regulation, Neoplastic
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / metabolism
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Kelch-Like ECH-Associated Protein 1
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Kidney Diseases, Cystic / genetics
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Kidney Diseases, Cystic / metabolism*
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Mice
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NF-E2-Related Factor 2 / metabolism*
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Procollagen-Proline Dioxygenase / metabolism
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Signal Transduction
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Succinates / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antioxidants
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Cytoskeletal Proteins
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Fumarates
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Hypoxia-Inducible Factor 1
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Succinates
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Procollagen-Proline Dioxygenase
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Fumarate Hydratase