title: F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress.
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.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Malonia
authors.affiliation: National Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune, Maharashtra 411007, India;
authors.forename: Parul
authors.initials: P
authors.lastname: Dutta
authors.affiliation: National Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune, Maharashtra 411007, India; manas@nccs.res.in Michael.Green@umassmed.edu.
authors.forename: Manas Kumar
authors.initials: MK
authors.lastname: Santra
authors.affiliation: 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.
authors.forename: Michael R
authors.identifier: http://orcid.org/0000-0003-3017-3298
authors.initials: MR
authors.lastname: Green
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage; D044783:F-Box Proteins / Q000502:physiology*; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D044783:F-Box Proteins; C507917:FBXO31 protein, human; D009153:Mutagens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage; FBXO31; MDM2; p53; tumor suppressor