Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling.
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.
Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
Julie
J
Adam
Emine
E
Hatipoglu
Linda
L
O'Flaherty
Nicola
N
Ternette
Natasha
N
Sahgal
Helen
H
Lockstone
Dilair
D
Baban
Emma
E
Nye
Gordon W
GW
Stamp
Kathryn
K
Wolhuter
Marcus
M
Stevens
Roman
R
Fischer
Peter
P
Carmeliet
Patrick H
PH
Maxwell
Chris W
CW
Pugh
Norma
N
Frizzell
Tomoyoshi
T
Soga
Benedikt M
BM
Kessler
Mona
M
El-Bahrawy
Peter J
PJ
Ratcliffe
Patrick J
PJ
Pollard
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015687:Cell Hypoxia; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005649:Fumarate Hydratase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005650:Fumarates / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D015398:Signal Transduction; D013386:Succinates / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D005650:Fumarates; D051793:Hypoxia-Inducible Factor 1; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D013386:Succinates; D011393:Procollagen-Proline Dioxygenase; D005649:Fumarate Hydratase