The negative role of cyclin G in ATM-dependent p53 activation
The negative role of cyclin G in ATM-dependent p53 activation
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DOI：
10.1038/sj.onc.1207693
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发表时间：
2004-07-08
期刊：
影响因子：
8
通讯作者：
Lee, SW
中科院分区：
文献类型：
--
作者：
Ohtsuka, T;Jensen, MR;Lee, SW
细胞周期蛋白G是最早被鉴定的p53靶基因之一，但其在p53通路中的功能一直是难以捉摸的。虽然细胞周期蛋白G在这个新的网络中的确切机制还没有被探索，但最近的研究表明，细胞周期蛋白G是p53-Mdm 2网络的关键调节因子。在这里，我们提出的证据表明，细胞周期蛋白G介导的p53调控依赖于共济失调毛细血管扩张突变（ATM）蛋白，激活p53在响应DNA损伤的状态。去除细胞周期蛋白G增强p53积累和p53在Ser-15残基的磷酸化，导致细胞周期停滞。在含有正常ATM的正常人真皮成纤维细胞中，异位表达的细胞周期蛋白G显着降低DNA损伤后p53的稳态水平以及Ser-15磷酸化p53的稳态水平。然而，细胞周期蛋白G不会引起ATM突变细胞中p53水平的类似降低。我们还表明，易位的细胞周期蛋白G的细胞核需要功能ATM。因此，我们的研究结果确定了一个新的作用，细胞周期蛋白G在ATM依赖的p53调控和DNA损伤过程中的细胞周期调控。
Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation of cyclin G enhances p53 accumulation and phosphorylation of p53 at the Ser-15 residue, resulting in cell cycle arrest. Ectopically expressed cyclin G significantly reduces the steady-state levels of p53 as well as that of phosphorylated p53 at Ser-15 after DNA damage in normal human dermal fibroblasts containing normal ATM. However, cyclin G does not cause similar reductions in p53 levels in ATM-mutated cells. We also show that translocation of cyclin G to the nucleus requires functional ATM. Thus, our findings identify a new role of cyclin G in ATM-dependent p53 regulation and in cell cycle regulation during DNA damage.