DNA damage stress induces the dissociation of Smurf1/2 from MDM2 in a slow manner

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• 作者：Jing Nie (1) (2)
  Lin Liu (3)
  XiaoHang Zhao (4)
  Ping Xie (2)
  PingKun Zhou (2)
  GuiChun Xing (2)
  XiangJun Liu (2)
  FuChu He (2)
  WeiDong Han (1)
  LingQiang Zhang (2)
  
• 关键词：Smurf1 ; MDM2 ; p53 ; DNA damage stress ; apoptosis
• 刊名：Chinese Science Bulletin
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：56
• 期：30
• 页码：3155-3161
• 全文大小：842KB
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• 作者单位：Jing Nie (1) (2)
  Lin Liu (3)
  XiaoHang Zhao (4)
  Ping Xie (2)
  PingKun Zhou (2)
  GuiChun Xing (2)
  XiangJun Liu (2)
  FuChu He (2)
  WeiDong Han (1)
  LingQiang Zhang (2)
  
  1. Department of Molecular Biology, General Hospital of Chinese People鈥檚 Liberation Army, Beijing, 100853, China
  2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China
  3. Department of General Surgery, General Hospital of Chinese People鈥檚 Liberation Army, Beijing, 100853, China
  4. State Key Laboratory of Molecular Oncology, Cancer Institute of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
  
• ISSN：1861-9541

文摘

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.