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dc.contributor.authorWhite, D
dc.contributor.authorUnwin, R
dc.contributor.authorBindels, E
dc.contributor.authorPierce, A
dc.contributor.authorTeng, H
dc.contributor.authorMuter, J
dc.contributor.authorGreystoke, Brigit F
dc.contributor.authorSomerville, Tim D D
dc.contributor.authorGriffiths, J
dc.contributor.authorLovell, S
dc.contributor.authorSomervaille, Tim C P
dc.contributor.authorDelwel, R
dc.contributor.authorWhetton, A
dc.contributor.authorMeyer, Stefan
dc.date.accessioned2013-08-06T14:41:50Zen
dc.date.available2013-08-06T14:41:50Zen
dc.date.issued2013en
dc.identifier.citationPhosphorylation of the leukemic oncoprotein EVI1 on serine 196 modulates DNA binding, transcriptional repression and transforming ability. 2013, 8 (6):e66510 PLoS ONEen_GB
dc.identifier.issn1932-6203en
dc.identifier.pmid23776681en
dc.identifier.doi10.1371/journal.pone.0066510en
dc.identifier.urihttp://hdl.handle.net/10541/297462en
dc.description.abstractThe EVI1 (ecotropic viral integration site 1) gene at 3q26 codes for a transcriptional regulator with an essential role in haematopoiesis. Overexpression of EVI1 in acute myeloid leukaemia (AML) is frequently associated with 3q26 rearrangements and confers extremely poor prognosis. EVI1 mediates transcriptional regulation, signalling, and epigenetic modifications by interacting with DNA, proteins and protein complexes. To explore to what extent protein phosphorylation impacts on EVI1 functions, we analysed endogenous EVI1 protein from a high EVI1 expressing Fanconi anaemia (FA) derived AML cell line. Mass spectrometric analysis of immunoprecipitated EVI1 revealed phosphorylation at serine 196 (S196) in the sixth zinc finger of the N-terminal zinc finger domain. Mutated EVI1 with an aspartate substitution at serine 196 (S196D), which mimics serine phosphorylation of this site, exhibited reduced DNA-binding and transcriptional repression from a gene promotor selectively targeted by the N-terminal zinc finger domain. Forced expression of the S196D mutant significantly reduced EVI1 mediated transformation of Rat1 fibroblasts. While EVI1-mediated serial replating of murine haematopoietic progenitors was maintained by EVI1-S196D, this was associated with significantly higher Evi1-trancript levels compared with WT-EVI1 or EVI1-S196A, mimicking S196 non-phosphorylated EVI1. These data suggest that EVI1 function is modulated by phosphorylation of the first zinc finger domain.
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.titlePhosphorylation of the leukemic oncoprotein EVI1 on serine 196 modulates DNA binding, transcriptional repression and transforming ability.en
dc.typeArticleen
dc.contributor.departmentStem Cell and Leukaemia Proteomics Laboratory, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.en_GB
dc.identifier.journalPLoS ONEen_GB
html.description.abstractThe EVI1 (ecotropic viral integration site 1) gene at 3q26 codes for a transcriptional regulator with an essential role in haematopoiesis. Overexpression of EVI1 in acute myeloid leukaemia (AML) is frequently associated with 3q26 rearrangements and confers extremely poor prognosis. EVI1 mediates transcriptional regulation, signalling, and epigenetic modifications by interacting with DNA, proteins and protein complexes. To explore to what extent protein phosphorylation impacts on EVI1 functions, we analysed endogenous EVI1 protein from a high EVI1 expressing Fanconi anaemia (FA) derived AML cell line. Mass spectrometric analysis of immunoprecipitated EVI1 revealed phosphorylation at serine 196 (S196) in the sixth zinc finger of the N-terminal zinc finger domain. Mutated EVI1 with an aspartate substitution at serine 196 (S196D), which mimics serine phosphorylation of this site, exhibited reduced DNA-binding and transcriptional repression from a gene promotor selectively targeted by the N-terminal zinc finger domain. Forced expression of the S196D mutant significantly reduced EVI1 mediated transformation of Rat1 fibroblasts. While EVI1-mediated serial replating of murine haematopoietic progenitors was maintained by EVI1-S196D, this was associated with significantly higher Evi1-trancript levels compared with WT-EVI1 or EVI1-S196A, mimicking S196 non-phosphorylated EVI1. These data suggest that EVI1 function is modulated by phosphorylation of the first zinc finger domain.


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