fumarates and Kidney-Diseases--Cystic

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.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antioxidants; Cell Hypoxia; Cytoskeletal Proteins; Fumarate Hydratase; Fumarates; Gene Expression Regulation, Neoplastic; Hypoxia-Inducible Factor 1; Kelch-Like ECH-Associated Protein 1; Kidney Diseases, Cystic; Mice; NF-E2-Related Factor 2; Procollagen-Proline Dioxygenase; Signal Transduction; Succinates