A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.
Cell
; 137(1): 87-98, 2009 Apr 03.
Article
em En
| MEDLINE
| ID: mdl-19345189
ABSTRACT
TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Proteína Supressora de Tumor p53
/
Fator de Crescimento Transformador beta
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Proteínas Supressoras de Tumor
/
Proteínas Smad
/
Metástase Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Itália