期刊
CANCER CELL
卷 20, 期 4, 页码 524-537出版社
CELL PRESS
DOI: 10.1016/j.ccr.2011.09.006
关键词
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资金
- UCARE (Oxford), Cancer Research UK [C6079/A9485, C10843/A12027]
- Wellcome Trust [WT091112MA, WT091857MA, 090532/Z/09/Z]
- Wellcome Trust Centre for Human Genetics, Oxford
- Biomedical Research Centre (NIHR), Oxford, UK
- Longterm structural Methusalem funding (Flemish Government)
- Fondation Leducq - Transatlantic Network Artemis
- Belgian Federation against Cancer [196-2008]
- Federal Government IUAP [P06/30]
- National Institute for Health Research [NF-SI-0507-10315] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [22134007] Funding Source: KAKEN
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.
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