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 Ratcliffe; Patrick J Pollard

doi: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

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

Deanery of Molecular, Genetic and Population Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 language	English
Pages (from-to)	524-37
Number of pages	14
Journal	Cancer Cell
Volume	20
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2011.09.006
Publication status	Published - 18 Oct 2011

Keywords / Materials (for Non-textual outputs)

Adaptor Proteins, Signal Transducing
Animals
Antioxidants
Cell Hypoxia
Cytoskeletal Proteins
Fumarate Hydratase
Fumarates
Gene Expression Regulation, Neoplastic
Hypoxia-Inducible Factor 1
Kidney Diseases, Cystic
Mice
NF-E2-Related Factor 2
Procollagen-Proline Dioxygenase
Signal Transduction
Succinates

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10.1016/j.ccr.2011.09.006

Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif-Phd Pathway
Copyright 2011 Elsevier Inc. Open Access funded by Wellcome Trust
Final published version, 2.36 MB

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Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., Stevens, M., Fischer, R., Carmeliet, P., Maxwell, P. H., Pugh, C. W., Frizzell, N., Soga, T., Kessler, B. M., El-Bahrawy, M., ... 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), 524-37. https://doi.org/10.1016/j.ccr.2011.09.006

@article{4c767c53cd9141ecb1f2225da1e2fd78,

title = "Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling",

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.",

keywords = "Adaptor Proteins, Signal Transducing, Animals, Antioxidants, Cell Hypoxia, Cytoskeletal Proteins, Fumarate Hydratase, Fumarates, Gene Expression Regulation, Neoplastic, Hypoxia-Inducible Factor 1, Kidney Diseases, Cystic, Mice, NF-E2-Related Factor 2, Procollagen-Proline Dioxygenase, Signal Transduction, Succinates",

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

year = "2011",

month = oct,

day = "18",

doi = "10.1016/j.ccr.2011.09.006",

language = "English",

volume = "20",

pages = "524--37",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

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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. 524-37. https://doi.org/10.1016/j.ccr.2011.09.006

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

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.

KW - Adaptor Proteins, Signal Transducing

KW - Animals

KW - Antioxidants

KW - Cell Hypoxia

KW - Cytoskeletal Proteins

KW - Fumarate Hydratase

KW - Fumarates

KW - Gene Expression Regulation, Neoplastic

KW - Hypoxia-Inducible Factor 1

KW - Kidney Diseases, Cystic

KW - Mice

KW - NF-E2-Related Factor 2

KW - Procollagen-Proline Dioxygenase

KW - Signal Transduction

KW - Succinates

U2 - 10.1016/j.ccr.2011.09.006

DO - 10.1016/j.ccr.2011.09.006

M3 - Article

C2 - 22014577

SN - 1535-6108

VL - 20

SP - 524

EP - 537

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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