The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Cell. 2009 Dec 24;139(7):1327-41. doi: 10.1016/j.cell.2009.11.026.
p53 is a tumor suppressor protein whose function is frequently lost in cancers through missense mutations within the Tp53 gene. This results in the expression of point-mutated p53 proteins that have both lost wild-type tumor suppressor activity and show gain of functions that contribute to transformation and metastasis. Here, we show that mutant p53 expression can promote invasion, loss of directionality of migration, and metastatic behavior. These activities of p53 reflect enhanced integrin and epidermal growth factor receptor (EGFR) trafficking, which depends on Rab-coupling protein (RCP) and results in constitutive activation of EGFR/integrin signaling. We provide evidence that mutant p53 promotes cell invasion via the inhibition of TAp63, and simultaneous loss of p53 and TAp63 recapitulates the phenotype of mutant p53 in cells. These findings open the possibility that blocking alpha5/beta1-integrin and/or the EGF receptor will have therapeutic benefit in mutant p53-expressing cancers.
p53 是一种肿瘤抑制蛋白，其功能通常通过 Tp53 基因中的错义突变而在癌症中丧失。这导致表达点突变的 p53 蛋白，其既失去野生型肿瘤抑制活性，又表现出促进转化和转移的功能。在这里，我们表明突变型 p53 的表达可以促进侵袭、迁移方向的丧失和转移行为。p53 的这些活性反映了整合素和表皮生长因子受体 (EGFR) 运输的增强，这依赖于 Rab 偶联蛋白 (RCP)，并导致 EGFR/整合素信号的组成性激活。我们提供的证据表明，突变型 p53 通过抑制 TAp63 促进细胞侵袭，同时缺失 p53 和 TAp63 可在细胞中再现突变型 p53 的表型。这些发现为阻断 alpha5/beta1-整合素和/或 EGFR 在表达突变型 p53 的癌症中具有治疗益处提供了可能性。
