Although both the p53 and forkhead box (FOX) family proteins are key transcription factors associated with cancer progression, their direct relationship is unknown. Here, we found that FOX family proteins bind to the non-canonical homotypic cluster of the p53 promoter region (TP53). Analysis of crystal structures of FOX proteins (FOXL2 and FOXA1) bound to the p53 homotypic cluster indicated that they interact with a 2:1 stoichiometry accommodated by FOX-induced DNA allostery. In particular, FOX proteins exhibited distinct dimerization patterns in recognition of the same p53-DNA; dimer formation of FOXA1 involved protein–protein interaction, but FOXL2 did not. Biochemical and biological functional analyses confirmed the cooperative binding of FOX proteins to the TP53 promoter for the transcriptional activation of TP53. In addition, up-regulation of TP53 was necessary for FOX proteins to exhibit anti-proliferative activity in cancer cells. These analyses reveal the presence of a discrete characteristic within FOX family proteins in which FOX proteins regulate the transcription activity of the p53 tumor suppressor via cooperative binding to the TP53 promoter in alternative dimer configurations.

中文翻译：

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FOXL2 和 FOXA1 在替代二聚体配置中协同组装在 TP53 启动子上

尽管 p53 和叉头盒 (FOX) 家族蛋白都是与癌症进展相关的关键转录因子，但它们的直接关系尚不清楚。在这里，我们发现 FOX 家族蛋白与 p53 启动子区域 (TP53) 的非典型同型簇结合。对与 p53 同型簇结合的 FOX 蛋白（FOXL2 和 FOXA1）的晶体结构分析表明，它们与 FOX 诱导的 DNA 变构所适应的 2:1 化学计量相互作用。特别是，FOX 蛋白在识别相同的 p53-DNA 时表现出不同的二聚化模式。FOXA1 的二聚体形成涉及蛋白质-蛋白质相互作用，但 FOXL2 没有。生化和生物功能分析证实了 FOX 蛋白与 TP53 启动子的协同结合，用于 TP53 的转录激活。此外，TP53的上调是FOX蛋白在癌细胞中表现出抗增殖活性所必需的。这些分析揭示了 FOX 家族蛋白中存在离散特征，其中 FOX 蛋白通过以替代二聚体配置与 TP53 启动子协同结合来调节 p53 肿瘤抑制因子的转录活性。