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

共 59 条

[1] S-(2-succinyl)cysteine:: A novel chemical modification of tissue proteins by a Krebs cycle intermediate [J].

Alderson, Nathan L. ;

Wang, Yuping ;

Blatnik, Matthew ;

Frizzell, Norma ;

Walla, Michael D. ;

Lyons, Timothy J. ;

Alt, Nadja ;

Carson, James A. ;

Nagai, Ryji ;

Thorpe, Suzanne R. ;

Baynes, John W. .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2006, 450 (01) :1-8

[2] Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism [J].

Aragones, Julian ;

Schneider, Martin ;

Van Geyte, Katie ;

Fraisl, Peter ;

Dresselaers, Tom ;

Mazzone, Massimiliano ;

Dirkx, Ruud ;

Zacchigna, Serena ;

Lemieux, Helene ;

Jeoung, Nam Ho ;

Lambrechts, Diether ;

Bishop, Tammie ;

Lafuste, Peggy ;

Diez-Juan, Antonio ;

Harten, Sarah K. ;

Van Noten, Pieter ;

De Bock, Katrien ;

Willam, Carsten ;

Tjwa, Marc ;

Grosfeld, Alexandra ;

Navet, Rachel ;

Moons, Lieve ;

Vandendriessche, Thierry ;

Deroose, Christophe ;

Wijeyekoon, Bhathiya ;

Nuyts, Johan ;

Jordan, Benedicte ;

Silasi-Mansat, Robert ;

Lupu, Florea ;

Dewerchin, Mieke ;

Pugh, Chris ;

Salmon, Phil ;

Mortelmans, Luc ;

Gallez, Bernard ;

Gorus, Frans ;

Buyse, Johan ;

Sluse, Francis ;

Harris, Robert A. ;

Gnaiger, Erich ;

Hespel, Peter ;

Van Hecke, Paul ;

Schuit, Frans ;

Van Veldhoven, Paul ;

Ratcliffe, Peter ;

Baes, Myriam ;

Maxwell, Patrick ;

Carmeliet, Peter .

NATURE GENETICS, 2008, 40 (02) :170-180

[3] Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis [J].

Ashrafian, Houman ;

O'Flaherty, Linda ;

Adam, Julie ;

Steeples, Violetta ;

Chung, Yuen-Li ;

East, Phil ;

Vanharanta, Sakari ;

Lehtonen, Heli ;

Nye, Emma ;

Hatipoglu, Emine ;

Miranda, Melroy ;

Howarth, Kimberley ;

Shukla, Deepa ;

Troy, Helen ;

Griffiths, John ;

Spencer-Dene, Bradley ;

Yusuf, Mohammed ;

Volpi, Emanuela ;

Maxwell, Patrick H. ;

Stamp, Gordon ;

Poulsom, Richard ;

Pugh, Christopher W. ;

Costa, Barbara ;

Bardella, Chiara ;

Di Renzo, Maria Flavia ;

Kotlikoff, Michael I. ;

Launonen, Virpi ;

Aaltonen, Lauri ;

El-Bahrawy, Mona ;

Tomlinson, Ian ;

Pollard, Patrick J. .

CANCER RESEARCH, 2010, 70 (22) :9153-9165

[4] Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status [J].

Bardella, Chiara ;

El-Bahrawy, Mona ;

Frizzell, Norma ;

Adam, Julie ;

Ternette, Nicola ;

Hatipoglu, Emine ;

Howarth, Kimberley ;

O'Flaherty, Linda ;

Roberts, Ian ;

Turner, Gareth ;

Taylor, Jennifer ;

Giaslakiotis, Konstantinos ;

Macaulay, Valentine M. ;

Harris, Adrian L. ;

Chandra, Ashish ;

Lehtonen, Heli J. ;

Launonen, Virpi ;

Aaltonen, Lauri A. ;

Pugh, Christopher W. ;

Mihai, Radu ;

Trudgian, David ;

Kessler, Benedikt ;

Baynes, John W. ;

Ratcliffe, Peter J. ;

Tomlinson, Ian P. ;

Pollard, Patrick J. .

JOURNAL OF PATHOLOGY, 2011, 225 (01) :4-11

[5] Succination of proteins by fumarate - Mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes [J].

Biatnik, Matthew ;

Thorpe, Suzanne R. ;

Baynes, John W. .

MAILLARD REACTION: RECENT ADVANCES IN FOOD AND BIOMEDICAL SCIENCES, 2008, 1126 :272-275

[6] Role of Nrf1 in antioxidant response element-mediated gene expression and beyond [J].

Biswas, Madhurima ;

Chan, Jefferson Y. .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2010, 244 (01) :16-20

[7] Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes - Formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress [J].

Blatnik, Matthew ;

Frizzell, Norma ;

Thorpe, Suzanne R. ;

Baynes, John W. .

DIABETES, 2008, 57 (01) :41-49

[8] Role of hypoxia-inducible factor (HIF)-1α-versus HIF-2α in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-1, or loss of von Hippel-Lindau function:: Implications for targeting the HIF pathway [J].

Carroll, Veronica A. ;

Ashcroft, Margaret .

CANCER RESEARCH, 2006, 66 (12) :6264-6270

[9] Mammalian zinc transport, trafficking, and signals [J].

Cousins, Robert J. ;

Liuzzi, Juan P. ;

Lichten, Louis A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (34) :24085-24089

[10] HIF-1α is essential for myeloid cell-mediated inflammation [J].

Cramer, T ;

Yamanishi, Y ;

Clausen, BE ;

Förster, I ;

Pawlinski, R ;

Mackman, N ;

Haase, VH ;

Jaenisch, R ;

Corr, M ;

Nizet, V ;

Firestein, GS ;

Gerber, HP ;

Ferrara, N ;

Johnson, RS .

CELL, 2003, 112 (05) :645-657

← 1 2 3 4 5 6 →