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.

Original publication

DOI

10.1016/j.ccr.2011.09.006

Type

Journal article

Journal

Cancer Cell

Publication Date

18/10/2011

Volume

20

Pages

524 - 537

Keywords

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