Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Graduate Group in Biochemistry and Biophysics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Genes Dev. 2018 Feb 1;32(3-4):230-243. doi: 10.1101/gad.309062.117. Epub 2018 Feb 20.
Mutant forms of p53 protein often possess protumorigenic functions, conferring increased survival and migration to tumor cells via their "gain-of-function" activity. Whether and how a common polymorphism in at amino acid 72 (Pro72Arg; referred to here as P72 and R72) impacts this gain of function has not been determined. We show that mutant p53 enhances migration and metastasis of tumors through the ability to bind and regulate PGC-1α and that this regulation is markedly impacted by the codon 72 polymorphism. Tumor cells with the R72 variant of mutant p53 show increased PGC-1α function along with greatly increased mitochondrial function and metastatic capability. Breast cancers containing mutant p53 and the R72 variant show poorer prognosis compared with P72. The combined results reveal PGC-1α as a novel "gain-of-function" partner of mutant p53 and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis.
p53 蛋白的突变形式通常具有促肿瘤发生的功能，通过其“功能获得”活性赋予肿瘤细胞更高的存活率和迁移能力。在第 72 位氨基酸（脯氨酸 72 位精氨酸；此处称为 P72 和 R72）的常见多态性是否以及如何影响这种功能获得尚未确定。我们表明，突变型 p53 通过结合和调节 PGC-1α 的能力增强肿瘤的迁移和转移，并且这种调节受密码子 72 多态性的显著影响。携带突变型 p53 的 R72 变体的肿瘤细胞显示出 PGC-1α 功能的增加，同时线粒体功能和转移能力大大增加。与 P72 相比，含有突变型 p53 和 R72 变体的乳腺癌预后较差。综合结果揭示了 PGC-1α 作为突变型 p53 的一种新的“功能获得”伴侣，并表明密码子 72 多态性影响突变型 p53 对代谢和转移的影响。
