Portal de Periódicos da CAPES

Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling

2011; Cell Press; Volume: 20; Issue: 4 Linguagem: Inglês

10.1016/j.ccr.2011.09.006

1878-3686

Julie Adam, Emine Hatipoglu, Linda O′Flaherty, Nicola Ternette, Natasha Sahgal, Helen Lockstone, Dilair Baban, Emma Nye, Gordon Stamp, Kathryn Wolhuter, Marcus Stevens, Román Fischer, Peter Carmeliet, Patrick H. Maxwell, Christopher W. Pugh, Norma Frizzell, Tomoyoshi Soga, Benedikt M. Kessler, Mona El‐Bahrawy, Peter J. Ratcliffe, Patrick J. Pollard,

Aldose Reductase and Taurine

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.