Regulation of Actinomycin D induced upregulation of Mdm2 in H1299 cells
Regulation of Actinomycin D induced upregulation of Mdm2 in H1299 cells
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Actinomycin D 的调节诱导 H1299 细胞中 Mdm2 的上调
DOI：
10.1016/j.dnarep.2011.10.010
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发表时间：
2012-02-01
期刊：
影响因子：
3.8
通讯作者：
Tang, Jun
中科院分区：
文献类型：
--
作者：
Li, Lianjie;Cui, Di;Tang, Jun
Mdm2是p53肿瘤抑制因子的重要负调节因子，并且也具有许多不依赖于p53的功能。Mdm 2的失调与肿瘤发生密切相关。然而，Mdm 2如何响应于各种应激而被调节还没有很好地理解。在这项研究中，我们发现，Mdm 2的稳定和上调后，放线菌素D（ActD）处理的p53缺陷型H1299细胞系。这种Mdm 2的上调不依赖于核糖体蛋白L11，核糖体应激诱导的p53激活的重要参与者，但确实需要NEDDylation依赖性机制。我们进一步证明了ActD诱导的Mdm 2稳定化可能受到细胞生长信号的调节，并且Mdm 2的敲低增强了H1299细胞中ActD诱导的细胞死亡。这些结果表明Mdm 2在p53缺陷细胞中的核糖体应激反应中的作用，其可用于治疗携带p53突变的癌症的治疗用途。(C)2011爱思唯尔有限公司版权所有。
Mdm2 is a critical negative regulator of the p53 tumor suppressor and also has many p53-independent functions. Deregulation of Mdm2 is closely associated with tumorigenesis. However, how Mdm2 is regulated in response to various stresses is not well understood. In this study, we found that Mdm2 was stabilized and upregulated upon Actinomycin D (ActD) treatment in the p53-deficient H1299 cell line. This Mdm2 upregulation was not dependent on the ribosomal protein L11, an essential player in ribosomal stress-induced p53 activation, but did require a NEDDylation-dependent mechanism. We further demonstrated that the ActD-induced Mdm2 stabilization may be modulated by the cell growth signaling, and that knockdown of Mdm2 enhanced ActD-induced cell death in H1299 cells. These results suggested a role of Mdm2 in the ribosomal stress response in the p53 deficient cells, which could be exploited in therapeutic use for treating cancers harboring p53 mutations. (C) 2011 Elsevier B.V. All rights reserved.