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

作　　者：NIE Jing LIU Lin ZHAO XiaoHang XIE Ping ZHOU PingKun XING GuiChun LIU XiangJun HE FuChu HAN WeiDong ZHANG LingQiang 

机构地区：[1]Department of Molecular Biology, General Hospital of Chinese People＇s Liberation Army, Beijing 100853, China [2]State Key Laboratory ofProteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China [3]Department of General Surgery, General Hospital of Chinese People＇s Liberation Army, Beijing 100853, China

出　　处：《Chinese Science Bulletin》2011年第30期3155-3161,共7页

基　　金：supported by the National Natural Science Foundation of China (31100554, 30800177);the National Basic Research Program of China (2007CB914601, 2011CB910802)

摘　　要：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.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 （Smurfl/2） promotes p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53. However, it is unclear how the Smurfl-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in response to etoposide treatment Smurfl dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The negative regulation of Smurfl on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response, implicating high expression of Smurfl might confer the resistance against p53 activation. Consistent with this notion, we observed that Smurfl/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer tissues, suggesting the oncogenic tendency of Smurfl/2.

关 键 词：DNA损伤 MDM2 应激反应 蛋白 解离 泛素连接酶 细胞凋亡 诱导 

分 类 号：Q523[生物学—生物化学] Q691.5