Tianjin Institute of Medical and Pharmaceutical Sciences, China.
Tianjin Medicine and Health Research Center, China.
FEBS Lett. 2023 Dec;597(24):3087-3101. doi: 10.1002/1873-3468.14774. Epub 2023 Nov 23.
Tumor-associated p53 mutations induce activities different from wild-type p53, thus causing loss of the protein's tumor inhibition function. The cells carrying p53 mutations have more aggressive characteristics related to invasion, metastasis, proliferation, and cell survival. By comparing the gene expression profiles of mutant p53 (mutp53) and mutp53 silenced cohorts, we found that FOS-related antigen-1 (FRA-1), which is encoded by FOSL1, is a potential effector of mutp53-mediated metastasis. We demonstrate that the expression of FRA-1, a gatekeeper of mesenchymal-epithelial transition, is elevated in the presence of p53 mutations. Mechanistically, mutant p53 cooperates with the transcription factor ELK1 in binding and activating the promoter of FOSL1, thus fostering lung metastasis. This study reveals new insights into how mutant p53 contributes to metastasis in breast cancer.
肿瘤相关的 p53 突变会诱导与野生型 p53 不同的活性，从而导致该蛋白的肿瘤抑制功能丧失。携带 p53 突变的细胞具有更强的侵袭、转移、增殖和细胞存活等相关特性。通过比较突变型 p53 (mutp53) 和 mutp53 沉默队列的基因表达谱，我们发现 FOS 相关抗原-1 (FRA-1)，即由 FOSL1 编码，是 mutp53 介导转移的潜在效应因子。我们证明，在存在 p53 突变的情况下，作为间质-上皮转化的守门员的 FRA-1 的表达升高。在机制上，突变型 p53 与转录因子 ELK1 合作，结合并激活 FOSL1 的启动子，从而促进肺转移。这项研究揭示了突变型 p53 如何促进乳腺癌转移的新见解。
