title: Regulation of p53 stability and function by the deubiquitinating enzyme USP42.
abstract: The p53 tumour suppressor protein is a transcription factor that prevents oncogenic progression by activating the expression of apoptosis and cell-cycle arrest genes in stressed cells. The stability of p53 is tightly regulated by ubiquitin-dependent degradation, driven mainly by the ubiquitin ligase MDM2. In this study, we have identified USP42 as a DUB that interacts with and deubiquitinates p53. USP42 forms a direct complex with p53 and controls level of ubiquitination during the early phase of the response to a range of stress signals. Although we do not find a clear role for USP42 in controlling either the basal or fully activated levels of p53, the function of USP42 is required to allow the rapid activation of p53-dependent transcription and a p53-dependent cell-cycle arrest in response to stress. These functions of USP42 are likely to contribute to the repair and recovery of cells from mild or transient damage.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Hock
authors.forename: Arnaud M
authors.initials: AM
authors.lastname: Vigneron
authors.forename: Stephanie
authors.initials: S
authors.lastname: Carter
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ludwig
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D006801:Humans; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C508707:USP42 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D013869:Thiolester Hydrolases
references.citation: Cell. 2010 Feb 5;140(3):384-96
references.pmid: 20096447
references.citation: Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83
references.pmid: 17380161
references.citation: Pathobiology. 2008;75(2):132-9
references.pmid: 18544968
references.citation: Adv Cancer Res. 2000;77:81-137
references.pmid: 10549356
references.citation: Cancer Cell. 2003 Jun;3(6):577-87
references.pmid: 12842086
references.citation: Nat Cell Biol. 2008 Jun;10(6):676-87
references.pmid: 18454141
references.citation: Cell. 1997 Oct 31;91(3):325-34
references.pmid: 9363941
references.citation: Cell Cycle. 2004 Jun;3(6):689-92
references.pmid: 15118411
references.citation: Mol Cell. 2005 May 27;18(5):565-76
references.pmid: 15916963
references.citation: Cold Spring Harb Perspect Biol. 2010 May;2(5):a001032
references.pmid: 20452958
references.citation: Nature. 2002 Apr 11;416(6881):648-53
references.pmid: 11923872
references.citation: EMBO J. 2011 Mar 2;30(5):846-58
references.pmid: 21285945
references.citation: J Biol Chem. 2000 Mar 24;275(12):8945-51
references.pmid: 10722742
references.citation: Mol Med. 1995 Jan;1(2):142-52
references.pmid: 8529093
references.citation: J Biol Chem. 2009 Feb 20;284(8):5030-41
references.pmid: 19098288
references.citation: Curr Cancer Drug Targets. 2005 Feb;5(1):3-8
references.pmid: 15720184
references.citation: Science. 2004 Feb 6;303(5659):844-8
references.pmid: 14704432
references.citation: Nature. 1995 Nov 9;378(6553):203-6
references.pmid: 7477326
references.citation: EMBO J. 2007 Jan 10;26(1):102-12
references.pmid: 17159902
references.citation: Cancer Cell. 2007 Oct;12(4):355-66
references.pmid: 17936560
references.citation: Cell. 2007 Aug 24;130(4):597-600
references.pmid: 17719538
references.citation: Nature. 1995 Nov 9;378(6553):206-8
references.pmid: 7477327
references.citation: Nat Rev Mol Cell Biol. 2009 Aug;10(8):550-63
references.pmid: 19626045
references.citation: Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
references.pmid: 18431400
references.citation: Mol Cell. 2004 Mar 26;13(6):879-86
references.pmid: 15053880
references.citation: Cell. 2005 Dec 2;123(5):773-86
references.pmid: 16325574
references.citation: Oncogene. 2007 Feb 26;26(9):1306-16
references.pmid: 17322916
references.citation: Gene Expr Patterns. 2007 Jan;7(1-2):143-8
references.pmid: 16904385
references.citation: EMBO J. 2007 Feb 21;26(4):976-86
references.pmid: 17290220
references.citation: Genes Dev. 2010 Nov 1;24(21):2430-9
references.pmid: 21041411
references.citation: Biochim Biophys Acta. 2009 May;1787(5):414-20
references.pmid: 19007744
references.citation: Mol Cell Biol. 1998 Jul;18(7):3692-8
references.pmid: 9632751