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标题：F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress
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作者：Sunil K. Malonia ; Parul Dutta ; Manas Kumar Santra 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8632-8637
DOI：10.1073/pnas.1510929112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe tumor suppressor protein p53 plays a critical role in protecting humans from cancer. In response to cellular stresses, such as DNA damage, p53 levels increase and induce a variety of protective biological responses. In unstressed cells, p53 is maintained at a low level by MDM2, a protein that interacts with p53 and promotes its degradation. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 levels. Because of the essential role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that, following DNA damage, the F-box protein FBXO31, a potential tumor suppressor, is responsible for promoting MDM2 degradation and therefore is essential for the increase in p53 levels. The tumor suppressor p53 plays a critical role in maintaining genomic stability. In response to genotoxic stress, p53 levels increase and induce cell-cycle arrest, senescence, or apoptosis, thereby preventing replication of damaged DNA. In unstressed cells, p53 is maintained at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its polyubiquitination, leading to the subsequent destruction of p53 by the 26S proteasome. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 stability. Because of the important role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that the F-box protein FBXO31, a candidate tumor suppressor encoded in 16q24.3 for which there is loss of heterozygosity in various solid tumors, is responsible for promoting MDM2 degradation. Following genotoxic stress, FBXO31 is phosphorylated by the DNA damage serine/threonine kinase ATM, resulting in increased levels of FBXO31. FBXO31 then interacts with and directs the degradation of MDM2, which is dependent on phosphorylation of MDM2 by ATM. FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage.
关键词：p53 ; MDM2 ; FBXO31 ; DNA damage ; tumor suppressor