TY - JOUR
T1 - Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway
T2 - Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling
AU - Adam, Julie
AU - Hatipoglu, Emine
AU - O'Flaherty, Linda
AU - Ternette, Nicola
AU - Sahgal, Natasha
AU - Lockstone, Helen
AU - Baban, Dilair
AU - Nye, Emma
AU - Stamp, Gordon W.
AU - Wolhuter, Kathryn
AU - Stevens, Marcus
AU - Fischer, Roman
AU - Carmeliet, Peter
AU - Maxwell, Patrick H.
AU - Pugh, Chris W.
AU - Frizzell, Norma
AU - Soga, Tomoyoshi
AU - Kessler, Benedikt M.
AU - El-Bahrawy, Mona
AU - Ratcliffe, Peter J.
AU - Pollard, Patrick J.
N1 - Funding Information:
The authors are grateful for financial support to UCARE (Oxford), Cancer Research UK; [C6079/A9485] to P.J.R. and P.J.P. and [C10843/A12027] to P.J.P.; The Wellcome Trust; [WT091112MA] to P.J.P., [WT091857MA] to P.J.R. and [090532/Z/09/Z] for core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford. P.J.P. is a Beit Memorial Fellow. B.M.K. is supported by the Biomedical Research Centre (NIHR), Oxford, UK. P.C. is grateful for funding from Longterm structural Methusalem funding (Flemish Government); Fondation Leducq - Transatlantic Network Artemis; Belgian Federation against Cancer (196-2008) and Federal Government IUAP Program (P06/30). The authors thank Randall Johnson, Celeste Simon, and Peter Igarashi for providing the Hif-1α, Hif-2α, and Ksp-Cre mice, respectively, and W. Marston Linehan (NCI/NIH) for the UOK 262 cells. The authors are grateful to the staff at the Oxford University Biomedical Services facilities, David Trudgian, Mikael Altun, Rebecca Konietzny, Melroy Miranda, Kaori Igarashi, Kaori Saito, Maki Ohishi, and Sana Ota for technical assistance and to Prof. John Baynes for critical reading of the manuscript. P.J.P. and N.F. have filed for a patent application [USC-268-P(849)] covering immunohistochemical screening with a 2SC antibody for determination of FH mutations. P.J.R., P.H.M., and C.W.P. are cofounders and shareholders in ReOx, Ltd.
PY - 2011/10/18
Y1 - 2011/10/18
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2011.09.006
DO - 10.1016/j.ccr.2011.09.006
M3 - Article
C2 - 22014577
AN - SCOPUS:80054767730
SN - 1535-6108
VL - 20
SP - 524
EP - 537
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
