Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome.
Nat Cell Biol
; 17(4): 511-23, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25774835
ABSTRACT
The functional significance of the overexpression of unmutated TAp73, a homologue of the tumour suppressor p53, in multiple human cancers is unclear, but raises the possibility of unidentified roles in promoting tumorigenesis. We show here that TAp73 is stabilized by hypoxia, a condition highly prevalent in tumours, through HIF-1α-mediated repression of the ubiquitin ligase Siah1, which targets TAp73 for degradation. Consequently, TAp73-deficient tumours are less vascular and reduced in size, and conversely, TAp73 overexpression leads to increased vasculature. Moreover, we show that TAp73 is a critical regulator of the angiogenic transcriptome and is sufficient to directly activate the expression of several angiogenic genes. Finally, expression of TAp73 positively correlates with these angiogenic genes in several human tumours, and the angiogenic gene signature is sufficient to segregate the TAp73(Hi)- from TAp73(Low)-expressing tumours. These data demonstrate a pro-angiogenic role for TAp73 in supporting tumorigenesis, providing a rationale for its overexpression in cancers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Proteínas Supressoras de Tumor
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Ubiquitina-Proteína Ligases
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Proteínas de Ligação a DNA
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Neoplasias
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Neovascularização Patológica
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2015
Tipo de documento:
Article