Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling.

Journal article

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.

Authors: Adam, J; Hatipoglu, E; O'Flaherty, L; Ternette, N; Sahgal, N

• Publication status: Published
• Journal: Cancer cell
• Volume: 20
• Issue: 4
• Pages: 524-537
• Publication date: 2011-10-01
• DOI: 10.1016/j.ccr.2011.09.006
• EISSN: 1878-3686
• ISSN: 1535-6108
• Language: English
• Keywords: Kidney Diseases, Cystic; Fumarates; Succinates; Procollagen-Proline Dioxygenase; Animals; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing; Hypoxia-Inducible Factor 1; Mice; Gene Expression Regulation, Neoplastic; Antioxidants; NF-E2-Related Factor 2; Cell Hypoxia; Fumarate Hydratase; Signal Transduction