Mutant p53-Expressing Cells Undergo Necroptosis via Cell Competition with the Neighboring Normal Epithelial Cells
Mutant p53-Expressing Cells Undergo Necroptosis via Cell Competition with the Neighboring Normal Epithelial Cells
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DOI：
10.1016/j.celrep.2018.05.081
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发表时间：
2018-06-26
期刊：
影响因子：
8.8
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
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作者：
Watanabe, Hirotaka;Ishibashi, Kojiro;Fujita, Yasuyuki
p53是一种肿瘤抑制蛋白，其错义突变常见于人类癌症中。在癌症的多步进展过程中，p53突变一般在中晚期积累，而早期则不然，其潜在机制尚不清楚。在这项研究中，利用哺乳动物细胞培养物和小鼠离体系统，我们证明当表达p53R273H或p53R175H的细胞被正常上皮细胞包围时，突变的p53细胞会发生坏死性凋亡并从上皮单层中挤出。当突变的 p53 细胞单独存在时，不会发生细胞死亡，表明坏死性凋亡是细胞与周围正常细胞竞争的结果。此外，当 p53R273H 突变发生在 RasV12 转化的上皮细胞内时，细胞死亡被强烈抑制，并且大多数表达 p53R273H 的细胞保持完整。这些结果表明，癌症发展中致癌突变的顺序可能由细胞竞争决定。
p53 is a tumor suppressor protein, and its missense mutations are frequently found in human cancers. During the multi-step progression of cancer, p53 mutations generally accumulate at the mid or late stage, but not in the early stage, and the underlying mechanism is still unclear. In this study, using mammalian cell culture and mouse ex vivo systems, we demonstrate that when p53R273H- or p53R175H-expressing cells are surrounded by normal epithelial cells, mutant p53 cells undergo necroptosis and are basally extruded from the epithelial monolayer. When mutant p53 cells alone are present, cell death does not occur, indicating that necroptosis results from cell competition with the surrounding normal cells. Furthermore, when p53R273H mutation occurs within RasV12-transformed epithelia, cell death is strongly suppressed and most of the p53R273H-expressing cells remain intact. These results suggest that the order of oncogenic mutations in cancer development could be dictated by cell competition.