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dc.contributor.authorKirschner, Kristina
dc.contributor.authorSamarajiwa, Shamith A.
dc.contributor.authorCairns, Jonathan M.
dc.contributor.authorMenon, Suraj
dc.contributor.authorPérez-Mancera, Pedro A.
dc.contributor.authorTomimatsu, Kosuke
dc.contributor.authorBermejo-Rodriguez, Camino
dc.contributor.authorIto, Yoko
dc.contributor.authorChandra, Tamir
dc.contributor.authorNarita, Masako
dc.contributor.authorLyons, Scott K.
dc.contributor.authorLynch, Andy G.
dc.contributor.authorKimura, Hiroshi
dc.contributor.authorOhbayashi, Tetsuya
dc.contributor.authorTavaré, Simon
dc.contributor.authorNarita, Masashi
dc.date.accessioned2017-08-15T13:30:08Z
dc.date.available2017-08-15T13:30:08Z
dc.date.issued2015-03-19
dc.identifier.citationKirschner , K , Samarajiwa , S A , Cairns , J M , Menon , S , Pérez-Mancera , P A , Tomimatsu , K , Bermejo-Rodriguez , C , Ito , Y , Chandra , T , Narita , M , Lyons , S K , Lynch , A G , Kimura , H , Ohbayashi , T , Tavaré , S & Narita , M 2015 , ' Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53 ' , PLoS Genetics , vol. 11 , no. 3 , e1005053 . https://doi.org/10.1371/journal.pgen.1005053en
dc.identifier.issn1553-7390
dc.identifier.otherPURE: 250731098
dc.identifier.otherPURE UUID: 7046d851-7317-4e56-82c1-eb466dadf663
dc.identifier.otherScopus: 84926378825
dc.identifier.otherORCID: /0000-0002-7876-7338/work/35946878
dc.identifier.urihttp://hdl.handle.net/10023/11475
dc.descriptionThis work was supported by the University of Cambridge; Cancer Research UK (C14303/A17197); Hutchison Whampoa. In addition, MasasN and TO were supported by the Human Frontier Science Program (RGY0078/2010); HK was supported by MEXT KAKENHI (Grant Numbers 25116005 and 26291071); KT was supported by the Japan Society for the Promotion of Science (24–8563).en
dc.description.abstractThe downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.
dc.format.extent28
dc.language.isoeng
dc.relation.ispartofPLoS Geneticsen
dc.rights© 2015 Kirschner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectQH301 Biologyen
dc.subjectQH426 Geneticsen
dc.subjectEcology, Evolution, Behavior and Systematicsen
dc.subjectMolecular Biologyen
dc.subjectGeneticsen
dc.subjectGenetics(clinical)en
dc.subjectCancer Researchen
dc.subjectDASen
dc.subject.lccQH301en
dc.subject.lccQH426en
dc.titlePhenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53en
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Statisticsen
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1005053
dc.description.statusPeer revieweden


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