Mello Stephano S, Valente Liz J, Raj Nitin, Seoane Jose A, Flowers Brittany M, McClendon Jacob, Bieging-Rolett Kathryn T, Lee Jonghyeob, Ivanochko Danton, Kozak Margaret M, Chang Daniel T, Longacre Teri A, Koong Albert C, Arrowsmith Cheryl H, Kim Seung K, Vogel Hannes, Wood Laura D, Hruban Ralph H, Curtis Christina, Attardi Laura D
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer Cell. 2017 Oct 9;32(4):460-473.e6. doi: 10.1016/j.ccell.2017.09.007.
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 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.
p53转录因子是胰腺癌进展的关键障碍。为了阐明一直难以捉摸的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情况。令人惊讶的是，p53 TAD2突变体表现为一种“超级肿瘤抑制因子”，具有增强的抑制胰腺癌和反式激活选定的p53靶基因（包括Ptpn14）的能力。Ptpn14编码Yap癌蛋白的负调节因子，与p53一样，对胰腺癌抑制是必需且充分的。我们发现p53缺陷会促进Yap信号传导，并且PTPN14和TP53突变在人类癌症中相互排斥。这些研究揭示了一条对p53介导的肿瘤抑制至关重要的p53-Ptpn14-Yap途径。
