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dc.contributor.authorBarroilhet, L
dc.contributor.authorYang, J
dc.contributor.authorHasselblatt, K
dc.contributor.authorParanal, RM
dc.contributor.authorNg, Shu-Kay
dc.contributor.authorRauh-Hain, JA
dc.contributor.authorWelch, WR
dc.contributor.authorBradner, JE
dc.contributor.authorBerkowitz, RS
dc.contributor.authorNg, S-W
dc.date.accessioned2017-05-03T14:21:23Z
dc.date.available2017-05-03T14:21:23Z
dc.date.issued2013
dc.date.modified2014-02-20T22:20:27Z
dc.identifier.issn09509232
dc.identifier.doi10.1038/onc.2012.38
dc.identifier.urihttp://hdl.handle.net/10072/56950
dc.description.abstractIn this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G1 cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.publisher.placeUnited Kingdom
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom3896
dc.relation.ispartofpageto3903
dc.relation.ispartofjournalOncogene
dc.relation.ispartofvolume32
dc.rights.retentionY
dc.subject.fieldofresearchMedical and Health Sciences not elsewhere classified
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode119999
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode1112
dc.titleC-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2013
gro.hasfulltextNo Full Text
gro.griffith.authorNg, Shu Kay Angus


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