Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK.
Oncogene. 2013 Jul 18;32(29):3461-9. doi: 10.1038/onc.2012.426. Epub 2012 Sep 17.
The RNA helicase p68 (DDX5) is an established co-activator of the p53 tumour suppressor that itself has a pivotal role in orchestrating the cellular response to DNA damage. Although several factors influence the biological outcome of p53 activation, the mechanisms governing the choice between cell-cycle arrest and apoptosis remain to be elucidated. In the present study, we show that, while p68 is critical for p53-mediated transactivation of the cell-cycle arrest gene p21(WAF1/CIP1), it is dispensable for induction of several pro-apoptotic genes in response to DNA damage. Moreover, p68 depletion results in a striking inhibition of recruitment of p53 and RNA Pol II to the p21 promoter but not to the Bax or PUMA promoters, providing an explanation for the selective effect on p21 induction. Importantly, these findings are mirrored in a novel inducible p68 knockout mouse model in which p68 depletion results in a selective inhibition of p21 induction in several tissues. Moreover, in the bone marrow, p68 depletion results in an increased sensitivity to γ-irradiation, consistent with an increased level of apoptosis. These data highlight a novel function of p68 as a modulator of the decision between p53-mediated growth arrest and apoptosis in vitro and in vivo.
RNA 解旋酶 p68（DDX5）是 p53 肿瘤抑制因子的公认共激活因子，而 p53 本身在协调细胞对 DNA 损伤的反应中起着关键作用。尽管有几个因素会影响 p53 激活的生物学结果，但决定细胞周期停滞和细胞凋亡之间选择的机制仍有待阐明。在本研究中，我们表明，虽然 p68 对于 p53 介导的细胞周期阻滞基因 p21（WAF1/CIP1）的转录激活至关重要，但对于 DNA 损伤诱导的几种促凋亡基因的诱导却是可有可无的。此外，p68 的耗竭导致 p53 和 RNA Pol II 向 p21 启动子的募集明显受到抑制，但向 Bax 或 PUMA 启动子的募集不受抑制，这为 p21 诱导的选择性作用提供了一个解释。重要的是，这些发现与一种新的诱导型 p68 敲除小鼠模型相吻合，在该模型中，p68 的耗竭导致几种组织中 p21 的诱导选择性抑制。此外，在骨髓中，p68 的耗竭导致对 γ 辐射的敏感性增加，与凋亡水平增加一致。这些数据突出了 p68 作为体外和体内 p53 介导的生长停滞和细胞凋亡之间决策的调节剂的新功能。
