TGFβ 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 TGFβ-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFβ 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 TGFβ-dependent inhibition of p63 function.

Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., et al. (2009). A Mutant-p53/Smad Complex Opposes p63 to Empower TGF beta-Induced Metastasis. CELL, 137(1), 87-98 [10.1016/j.cell.2009.01.039].

A Mutant-p53/Smad Complex Opposes p63 to Empower TGF beta-Induced Metastasis

SOLARI, ALDO;
2009

Abstract

TGFβ 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 TGFβ-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFβ 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 TGFβ-dependent inhibition of p63 function.
Articolo in rivista - Articolo scientifico
signaling;
English
2009
137
1
87
98
none
Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., et al. (2009). A Mutant-p53/Smad Complex Opposes p63 to Empower TGF beta-Induced Metastasis. CELL, 137(1), 87-98 [10.1016/j.cell.2009.01.039].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/20200
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