Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Nat Commun. 2021 Jan 29;12(1):704. doi: 10.1038/s41467-021-20928-8.
p53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3 phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions. Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of oncogenesis.
癌症中 p53 点突变导致单一氨基酸改变，常导致显性致癌变化。在这里，我们利用条件性激活的 LSL p53-R172H 和 LSL K-Ras-G12D 敲入等位基因，在肺 club 细胞中利用 Cre 激活，开发了一种 p53 驱动的肺癌获得性功能（GOF）的小鼠模型。p53 转录激活域（TAD）（p53-L25Q/W26S/R172H）突变消除了显著的转录激活活性，导致肿瘤发生能力丧失，表明 GOF p53 的致癌性需要 TAD 介导或依赖的转录激活。GOF p53 TAD 突变显著降低了附近 p53 丝氨酸 20（S20）的磷酸化，S20 是 PLK3 磷酸化的靶点。敲除 PLK3 减弱了 GOF p53 的 S20 磷酸化、转录激活和致癌性，表明 GOF p53 利用 PLK3 触发其转录激活能力并发挥致癌功能。我们的数据表明，PLK3 参与了突变型 p53 致癌途径的机制。
