Title: Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling
Authors: 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 #
Issue Date: Oct-2011
Publisher: Cell Press
Series Title: Cancer Cell vol:20 issue:4 pages:524-537
Abstract: 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.
ISSN: 1535-6108
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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