TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation.
Proc Natl Acad Sci U S A
; 112(1): 226-31, 2015 Jan 06.
Article
em En
| MEDLINE
| ID: mdl-25535359
ABSTRACT
Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
/
Proteínas Supressoras de Tumor
/
Proteínas de Ligação a DNA
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Proteólise
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2015
Tipo de documento:
Article