DNA damage stress induces the dissociation of Smurf1/2 from MDM2 in a slow manner
DNA damage stress induces the dissociation of Smurf1/2 from MDM2 in a slow manner
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DOI：
10.1007/s11434-011-4703-9
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发表时间：
2011-10
影响因子：
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通讯作者：
J. Nie;Lin Liu;Xiaohang Zhao;P. Xie;P. Zhou;G. Xing;Xiangjun Liu;F. He;W. Han;Lingqiang Zhang
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文献类型：
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作者：
J. Nie;Lin Liu;Xiaohang Zhao;P. Xie;P. Zhou;G. Xing;Xiangjun Liu;F. He;W. Han;Lingqiang Zhang
抑癌基因p53位于细胞生长或凋亡平衡的关键点，其表达水平受包括MDM 2在内的泛素连接酶的严格控制。在DNA损伤应激时，p53积聚并激活，导致细胞周期停滞或凋亡。我们以前发现，Smad泛素化调节因子1/2（Smurf 1/2）通过与MDM 2相互作用并稳定MDM 2，从而增强MDM 2介导的p53泛素化，从而促进p53降解。然而，目前还不清楚Smurf 1-MDM 2相互作用是如何响应DNA损伤应激而调节的。在这里，我们表明，在响应依托泊苷治疗Smurf 1从MDM 2解离，导致MDM 2不稳定和p53积累。Smurf 1对细胞凋亡的负调节作用被解除。值得注意的是，这种解离是一个缓慢的过程，而不是一个快速的反应，暗示Smurf 1的高表达可能赋予对p53激活的抗性。与此一致，我们观察到Smurf 1/2连接酶在结肠癌、食管鳞状细胞癌和胰腺癌组织中高度表达，提示Smurf 1/2的致癌倾向。
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53. However, it is unclear how the Smurf1-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in response to etoposide treatment Smurf1 dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The negative regulation of Smurf1 on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response, implicating high expression of Smurf1 might confer the resistance against p53 activation. Consistent with this notion, we observed that Smurf1/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer tissues, suggesting the oncogenic tendency of Smurf1/2.