DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation
DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation
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DOI：
10.1091/mbc.e05-09-0858
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发表时间：
2006-04-01
影响因子：
3.3
通讯作者：
Ferbeyre, G
中科院分区：
文献类型：
--
作者：
Moiseeva, O;Mallette, FA;Ferbeyre, G
干扰素是一种细胞因子，具有很强的抗病毒和抗增殖活性。我们报道，尽管短暂暴露于β-干扰素会导致可逆的细胞周期停滞，但持续治疗会触发依赖于p53的衰老程序。β-干扰素分两步启动了P53。首先，它诱导了P53在赖氨酸320位的乙酰化和丝氨酸392位的去磷酸化，但不能诱导P53的活性。后来，它触发了DNA信号通路，丝氨酸15处P53的磷酸化及其转录活性。一致的是，β-干扰素处理的细胞积累了伽马-H_2AX焦点和磷酸化形式的ATM和Chk2。DNA损伤信号通路由干扰素诱导的ROS增加激活，并被抗氧化剂N-乙酰半胱氨酸抑制。更重要的是，针对ATM的RNA干扰抑制了P53丝氨酸15的磷酸化，抑制了P53活性和对β-干扰素的衰老反应。在表达P53或ERK2或RasV12的构成等位基因的细胞中，β-干扰素诱导的衰老更有效。因此，β-干扰素诱导的衰老优先针对有癌前病变的细胞。
Interferons are cytokines with potent antiviral and antiproliferative activities. We report that although a transient exposure to beta-interferon induces a reversible cell cycle arrest, a sustained treatment triggers a p53-dependent senescence program. beta-Interferon switched on p53 in two steps. First, it induced the acetylation of p53 at lysine 320 and its dephosphorylation at serine 392 but not p53 activity. Later on, it triggered a DNA signaling pathway, the phosphorylation of p53 at serine 15 and its transcriptional activity. In agreement, beta-interferon-treated cells accumulated gamma-H2AX foci and phosphorylated forms of ATM and CHK2. The DNA damage signaling pathway was activated by an increase in reactive oxygen species (ROS) induced by interferon and was inhibited by the antioxidant N-acetyl cysteine. More important, RNA interference against ATM inhibited p53 phosphorylation at serine 15, p53 activity and senescence in response to beta-interferon. beta-Interferon-induced senescence was more efficient in cells expressing either, p53, or constitutive allele of ERK2 or RasV12. Hence, beta-interferon-induced senescence targets preferentially cells with premalignant changes.