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, 2011 Oct 18.
Article
em En
| MEDLINE
| ID: mdl-22014577
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Succinatos
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Proteínas do Citoesqueleto
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Proteínas Adaptadoras de Transdução de Sinal
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Doenças Renais Císticas
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Fator 2 Relacionado a NF-E2
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Fumarato Hidratase
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Fumaratos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cancer Cell
Ano de publicação:
2011
Tipo de documento:
Article