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

Julie Adam, Emine Hatipoglu, Linda O'Flaherty, Nicola Ternette, Natasha Sahgal, Helen Lockstone, Dilair Baban, Emma Nye, Gordon W. Stamp, Kathryn Wolhuter, Marcus Stevens, Roman Fischer, Peter Carmeliet, Patrick H. Maxwell, Chris W. Pugh, Norma Frizzell, Tomoyoshi Soga, Benedikt M. Kessler, Mona El-Bahrawy, Peter J. RatcliffePatrick J. Pollard

研究成果: Article査読

373 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)524-537
ページ数14
ジャーナルCancer Cell
20
4
DOI
出版ステータスPublished - 2011 10 18

ASJC Scopus subject areas

  • 腫瘍学
  • 細胞生物学
  • 癌研究

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