Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
Oncogene. 2013 Dec 5;32(49):5531-40. doi: 10.1038/onc.2013.213. Epub 2013 Jun 10.
S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.
S100A4 是一种小的钙结合蛋白，在多种不同的肿瘤类型中普遍过表达，人们普遍认为 S100A4 在癌症转移过程中具有重要作用。体外结合实验表明，S100A4 与肿瘤抑制蛋白 p53 相互作用，表明 S100A4 在肿瘤发生发展过程中可能具有额外的作用。在本研究中，我们表明内源性 S100A4 和 p53 在复杂样本中相互作用，并且在用 Nutlin-3A 抑制 MDM2 依赖性 p53 降解后，这种相互作用增加。此外，使用邻近连接测定法，我们表明这种相互作用发生在细胞核中。在两个 p53 野生型细胞系 A549 和 HeLa 中进行 S100A4 敲低实验导致 p53 蛋白稳定，表明 S100A4 促进了 p53 的降解。最后，我们证明 S100A4 敲低导致 p53 依赖性细胞周期停滞和增加顺铂诱导的细胞凋亡。因此，我们的数据通过其抑制 p53 依赖性过程，为 S100A4 的致癌特性增添了新的内容。
