Author/Authors :
Adam، نويسنده , , Julie and Hatipoglu، نويسنده , , Emine and OʹFlaherty، نويسنده , , Linda and Ternette، نويسنده , , Nicola and Sahgal، نويسنده , , Natasha and Lockstone، نويسنده , , Helen and Baban، نويسنده , , Dilair and Nye، نويسنده , , Emma and Stamp، نويسنده , , Gordon W. and Wolhuter، نويسنده , , Kathryn and Stevens، نويسنده , , Marcus and Fischer، نويسنده , , Roman and Carmeliet، نويسنده , , Peter and Maxwell، نويسنده , , Patrick H. and Pugh، نويسنده , , Chris W. and Frizzell، نويسنده , , Norma and Soga، نويسنده , , Tomoyoshi and Kessler، نويسنده , , Benedikt M. and El-Bahrawy، نويسنده , , Mona and Ratcliffe، نويسنده , , Peter J. and Pollard، نويسنده , , Patrick J.، نويسنده ,
Abstract :
Summary
ebs 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.
