一种突变型p53/Smad复合物对抗p63以增强TGFβ诱导的转移。

A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

作者信息

Adorno Maddalena, Cordenonsi Michelangelo, Montagner Marco, Dupont Sirio, Wong Christine, Hann Byron, Solari Aldo, Bobisse Sara, Rondina Maria Beatrice, Guzzardo Vincenza, Parenti Anna R, Rosato Antonio, Bicciato Silvio, Balmain Allan, Piccolo Stefano

机构信息

Department of Histology, Microbiology and Medical Biotechnologies, University of Padua School of Medicine, viale Colombo 3, 35100 Padua, Italy.

出版信息

Cell. 2009 Apr 3;137(1):87-98. doi: 10.1016/j.cell.2009.01.039.

DOI:10.1016/j.cell.2009.01.039

PMID: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.

摘要

转化生长因子β（TGFβ）配体在早期肿瘤中作为肿瘤抑制因子起作用，但在晚期癌症中却反常地转变为强大的促转移因子。这种转变的分子本质仍然是个谜。在这里，我们表明，TGFβ依赖的细胞迁移、侵袭和转移由突变型p53驱动，并受到p63的抑制。从机制上讲，TGFβ与致癌性Ras和突变型p53协同作用，诱导形成一种突变型p53/p63蛋白复合物，其中Smads作为关键平台。在这个三元复合物中，p63的功能受到拮抗。在p63的下游，我们在一大群乳腺癌患者中鉴定出两个与转移风险相关的候选转移抑制基因。因此，在早期肿瘤中选择的两种常见致癌病变，即突变型p53和Ras，在促进生长和存活的同时，也通过TGFβ依赖的p63功能抑制，预示了一种具有特定转移倾向的细胞状态。