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

被引：469

作者：

Adam, Julie ^{[1
]}

Hatipoglu, Emine ^{[1
]}

O'Flaherty, Linda ^{[1
]}

Ternette, Nicola ^{[1
]}

Sahgal, Natasha ^{[2
]}

Lockstone, Helen ^{[2
]}

Baban, Dilair ^{[2
]}

Nye, Emma ^{[3
]}

Stamp, Gordon W. ^{[3
,4
]}

Wolhuter, Kathryn ^{[1
]}

Stevens, Marcus ^{[1
]}

Fischer, Roman ^{[1
]}

Carmeliet, Peter ^{[5
,6
]}

Maxwell, Patrick H. ^{[7
]}

Pugh, Chris W. ^{[1
]}

Frizzell, Norma ^{[8
]}

Soga, Tomoyoshi ^{[9
]}

Kessler, Benedikt M. ^{[1
]}

El-Bahrawy, Mona ^{[10
]}

Ratcliffe, Peter J. ^{[1
]}

Pollard, Patrick J. ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Oxford OX3 7BN, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[3] Canc Res UK London Res Inst, Expt Histopathol Lab, London WC2A 3LY, England

[4] Royal Marsden Hosp, Dept Histopathol, London WC2A 3LY, England

[5] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[6] Katholieke Univ Leuven, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[7] UCL, Div Med, London WC1E 6JF, England

[8] Univ S Carolina, Dept Exercise Sci, Sch Publ Hlth, Columbia, SC 29208 USA

[9] Keio Univ, Inst Adv Biosci, Yamagata 9970017, Japan

[10] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Histopathol, London W12 0NN, England

来源：

CANCER CELL | 2011年 / 20卷 / 04期

基金：

英国惠康基金;

关键词：

LINDAU TUMOR-SUPPRESSOR; HYDROXYLASE DOMAIN PROTEINS; HYPOXIA-INDUCIBLE FACTOR-1; CELL CARCINOMA; HEREDITARY LEIOMYOMATOSIS; CHEMICAL-MODIFICATION; MITOCHONDRIAL STRESS; HYDRATASE DEFICIENCY; RESPONSE ELEMENT; CANCER;

D O I：

10.1016/j.ccr.2011.09.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：524 / 537

页数：14

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