Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling
Adam, Julie × Hatipoglu, Emine O'Flaherty, Linda Ternette, Nicola Sahgal, Natasha Lockstone, Helen Baban, Dilair Nye, Emma Stamp, Gordon W Wolhuter, Kathryn Stevens, Marcus Fischer, Roman Carmeliet, Peter Maxwell, Patrick H Pugh, Chris W Frizzell, Norma Soga, Tomoyoshi Kessler, Benedikt M El-Bahrawy, Mona Ratcliffe, Peter J Pollard, Patrick J #
Cancer Cell vol:20 issue:4 pages:524-537
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.