The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53^53,54 TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

中文翻译：

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一个p53的超肿瘤抑制因子揭示了胰腺癌中一个肿瘤抑制性的p53-Ptpn14-Yap轴。

p53转录因子是胰腺癌进展的关键障碍。为了揭示仍难以捉摸的p53介导的肿瘤抑制机制，我们分析了表达p53转录激活域（TAD）突变体的小鼠的胰腺癌发展。令人惊讶的是p53 ^53,54TAD2突变体可充当“超肿瘤抑制因子”，具有增强的抑制胰腺癌和反激活包括ptpn14在内的选定p53靶基因的能力。Ptpn14编码Yap癌蛋白的负调节剂，对于抑制胰腺癌（如p53）是必要和充分的。我们显示p53缺乏促进Yap信号和PTPN14和TP53突变在人类癌症中是互斥的。这些研究揭示了p53-Ptpn14-Yap途径，该途径是p53介导的肿瘤抑制必不可少的。