Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Mol Cell. 2013 Jun 6;50(5):699-710. doi: 10.1016/j.molcel.2013.04.013. Epub 2013 May 16.
Oncogene-induced senescence is an important tumor-suppressing defense mechanism. However, relatively little is known about the signaling pathway mediating the senescence response. Here, we demonstrate that a multifunctional acetyltransferase, Tip60, plays an essential role in oncogenic ras-induced senescence. Further investigation reveals a cascade of posttranslational modifications involving p38, Tip60, and PRAK, three proteins that are essential for ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158; activated Tip60 in turn directly interacts with and induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the prosenescent function of Tip60 and PRAK, respectively. These results have defined a signaling pathway that mediates oncogene-induced senescence, and identified posttranslational modifications that regulate the enzymatic activity and biological functions of Tip60 and PRAK.
癌基因诱导的衰老（Oncogene-induced senescence）是一种重要的肿瘤抑制防御机制。然而，介导衰老反应的信号通路相对知之甚少。在这里，我们证明了多功能乙酰转移酶 Tip60 在致癌性 ras 诱导的衰老中发挥着重要作用。进一步的研究揭示了一系列涉及 p38、Tip60 和 PRAK 的翻译后修饰，这三种蛋白对于 ras 诱导的衰老至关重要。ras 激活后，p38 通过磷酸化 Thr158 诱导 Tip60 的乙酰转移酶活性；活化的 Tip60 反过来通过乙酰化 K364 直接与 PRAK 相互作用并诱导其蛋白激酶活性，这种相互作用方式依赖于 p38 对 Tip60 和 PRAK 的磷酸化。这些翻译后修饰分别对 Tip60 和 PRAK 的衰老前功能至关重要。这些结果定义了一条介导癌基因诱导衰老的信号通路，并确定了调节 Tip60 和 PRAK 的酶活性和生物学功能的翻译后修饰。
