Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
Cancer Cell
; 7(1): 77-85, 2005 Jan.
Article
em En
| MEDLINE
| ID: mdl-15652751
ABSTRACT
Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oncogenes
/
Fatores de Transcrição
/
Ciclo do Ácido Cítrico
/
Pró-Colágeno-Prolina Dioxigenase
/
Ácido Succínico
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article