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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)524-537
Number of pages14
JournalCancer Cell
Volume20
Issue number4
DOIs
Publication statusPublished - 2011 Oct 18

Fingerprint

Fumarates
Fumarate Hydratase
Cysts
Kidney
Antioxidants
Prolyl Hydroxylases
Neoplasms
Citric Acid Cycle
Genetic Models
Leiomyoma
Gene Expression Profiling
Cysteine
Carcinogenesis
Up-Regulation
Enzymes
Kelch-Like ECH-Associated Protein 1
Hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., ... Pollard, P. J. (2011). Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling. Cancer Cell, 20(4), 524-537. https://doi.org/10.1016/j.ccr.2011.09.006

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

In: Cancer Cell, Vol. 20, No. 4, 18.10.2011, p. 524-537.

Research output: Contribution to journalArticle

Adam, J, Hatipoglu, E, O'Flaherty, L, Ternette, N, Sahgal, N, Lockstone, H, Baban, D, Nye, E, Stamp, GW, Wolhuter, K, Stevens, M, Fischer, R, Carmeliet, P, Maxwell, PH, Pugh, CW, Frizzell, N, Soga, T, Kessler, BM, El-Bahrawy, M, Ratcliffe, PJ & Pollard, PJ 2011, 'Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling', Cancer Cell, vol. 20, no. 4, pp. 524-537. https://doi.org/10.1016/j.ccr.2011.09.006
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. / Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway : Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling. In: Cancer Cell. 2011 ; Vol. 20, No. 4. pp. 524-537.
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