A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis
A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis
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DOI：
10.1016/j.cell.2009.01.039
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发表时间：
2009-04-02
期刊：
影响因子：
64.5
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Adorno, Maddalena;Cordenonsi, Michelangelo;Piccolo, Stefano
TGF β配体在早期肿瘤中充当肿瘤抑制剂，但在晚期癌症中矛盾地转变为有效的促转移因子。这个开关的分子本质仍然是个谜。在这里，我们表明，TGF β依赖性细胞迁移，侵袭和转移是由muplant-p53和p63反对授权。从机制上讲，TGF β与致癌Ras和muplum-p53协同作用，诱导muplum-p53/p63蛋白复合物的组装，其中Smads作为必需的平台。在这种三元复合物中，p63功能被拮抗。在p63下游，我们在一个大的乳腺癌患者队列中鉴定了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的致癌性病变，即muplant-p53和Ras，通过TGF β依赖性抑制p63功能，也预示着具有特定转移倾向的细胞设置。
TGF beta 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 TGF beta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGF beta 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 TGF beta-dependent inhibition of p63 function.