Cancer Cell
Volume 20, Issue 4, 18 October 2011, Pages 524-537
Journal home page for Cancer Cell

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

https://doi.org/10.1016/j.ccr.2011.09.006Get rights and content
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Summary

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.

Highlights

► Fh1-associated renal cyst formation is independent of Hif/Phd pathway ► Nrf2-mediated antioxidant response pathway is upregulated following Fh1 loss ► Fumarate modifies cysteine residues in Keap1 by succination

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These authors contributed equally