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

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          Abstract

          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.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          Proceedings of the National Academy of Sciences
          1091-6490
          0027-8424
          Jul 14 2015
          : 112
          : 28
          Affiliations
          [1 ] Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
          [2 ] National Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune, Maharashtra 411007, India;
          [3 ] National Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune, Maharashtra 411007, India; manas@nccs.res.in Michael.Green@umassmed.edu.
          [4 ] Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605 manas@nccs.res.in Michael.Green@umassmed.edu.
          Article
          1510929112
          10.1073/pnas.1510929112
          4507212
          26124108
          9de94285-2675-4841-adc7-b91a5db17860
          History

          DNA damage,FBXO31,MDM2,p53,tumor suppressor
          DNA damage, FBXO31, MDM2, p53, tumor suppressor

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