Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens, GR-11527, Greece.
Nat Cell Biol. 2013 Aug;15(8):967-77. doi: 10.1038/ncb2795. Epub 2013 Jul 14.
The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.
DNA 损伤反应 (DDR) 途径和 ARF 作为癌症发展的障碍。尽管通常被认为彼此独立运作，但一些研究提出 ARF 受到 DDR 的正向调节。与上述任何一种情况都相反，我们发现在人类致癌基因转化和癌细胞中，ATM 通过非转录方式抑制 ARF 蛋白水平和活性。在机制上，ATM 激活蛋白磷酸酶 1，其拮抗 Nek2 依赖性核仁磷酸化蛋白 (NPM) 的磷酸化，从而使 ARF 从 NPM 中释放出来，并使其易于被 ULF E3 泛素连接酶降解。在人类临床样本中，ATM 表达缺失与 ARF 水平升高相关，在异种移植和组织培养模型中，抑制 ATM 可刺激 ARF 的肿瘤抑制作用。这些结果为 DDR 和 ARF 抗癌屏障之间的功能相互作用提供了深入了解，对肿瘤发生和晚期肿瘤的治疗具有重要意义。
