F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress

被引:52
作者
Malonia, Sunil K. [1 ]
Dutta, Parul [2 ]
Santra, Manas Kumar [2 ]
Green, Michael R. [1 ,3 ]
机构
[1] Univ Massachusetts, Dept Mol Cell & Canc Biol, Sch Med, Worcester, MA 01605 USA
[2] Natl Ctr Cell Sci, Pune 411007, Maharashtra, India
[3] Univ Massachusetts, Howard Hughes Med Inst, Sch Med, Worcester, MA 01605 USA
关键词
p53; MDM2; FBXO31; DNA damage; tumor suppressor; ATM-DEPENDENT PHOSPHORYLATION; UBIQUITIN LIGASE ACTIVITY; DNA-DAMAGE; TUMOR-SUPPRESSOR; KINASE ATM; P53; SENESCENCE; INHIBITOR; PROMOTES; CANCER;
D O I
10.1073/pnas.1510929112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:8632 / 8637
页数:6
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