Proteomic and interactome approaches reveal PAK4, PHB-2, and 14-3-3n as targets of overactivated Cdc42 in cellular responses to genomic instability

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dc.contributorLaboratório Especial de Toxinologia Aplicada (LETA)pt_BR
dc.contributor.authorSilva, Luiz E.pt_BR
dc.contributor.authorSouza, Renan C.pt_BR
dc.contributor.authorKitano, Eduardo Shigueopt_BR
dc.contributor.authorMonteiro, Lucas F.pt_BR
dc.contributor.authorIwai, Leo Keipt_BR
dc.contributor.authorForti, Fabio L.pt_BR
dc.date.accessioned2020-07-09T21:25:31Z-
dc.date.available2020-07-09T21:25:31Z-
dc.date.issued2019-
dc.identifier.citationSilva LE., Souza RC., Kitano ES, Monteiro LF., Iwai LK, Forti FL.. Proteomic and interactome approaches reveal PAK4, PHB-2, and 14-3-3n as targets of overactivated Cdc42 in cellular responses to genomic instability. J. proteome res.. 2019 Sep;18(10):3597-3614. doi:10.1021/acs.jproteome.9b00260.pt_BR
dc.identifier.issn1535-3893-
dc.identifier.issn1535-3907-
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2864-
dc.description.abstractCdc42, a member of the Rho GTPase family, is an intracellular signaling protein known for its roles in cytoskeleton rearrangements and, more recently, in apoptosis/senescence triggered by genotoxic stress. In some tumor cells, the overactivation of Cdc42 through the expression of constitutively active mutants (G12V or Q61L), GEF activation, or GAP downregulation functions as an antiproliferative or pro-aging mechanism. In this study, human cell lines with different P53 protein profiles were exposed to UV radiation, and the interactions between Cdc42 and proteins that are putatively involved in the DNA damage response and repair mechanisms were screened. The affinity-purified proteins obtained through pull-down experiments of the cell lysates using the recombinant protein baits GST, GST-Cdc42-WT, or GST-Cdc42-G12V were identified by mass spectrometry. The resulting data were filtered and used for the construction of protein–protein interaction networks. Among several promising proteins, three targets, namely, PAK4, PHB-2, and 14-3-3?, which are involved in the cell cycle, apoptosis, DNA repair, and chromatin remodeling processes, were identified. Biochemical validation experiments showed physical and proximal interactions between Cdc42 and the three targets in the cells, particularly after exposure to UV. The results suggest that the molecular mechanisms coordinated by overactivated Cdc42 (with the G12V mutation) to increase the cellular sensitivity to UV radiation and the susceptibility to cell death are collectively mediated by these three proteins. Therefore, the Cdc42 GTPase can potentially be considered another player involved in maintenance of the genomic stability of human cells during exposure to genotoxic stress.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.format.extent3597-3614pt_BR
dc.languageengpt_BR
dc.publisherAmerican Chemical Societypt_BR
dc.relation.ispartofJournal of Proteome Researchpt_BR
dc.titleProteomic and interactome approaches reveal PAK4, PHB-2, and 14-3-3n as targets of overactivated Cdc42 in cellular responses to genomic instabilitypt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1021/acs.jproteome.9b00260pt_BR
dc.identifier.urlhttps://doi.org/10.1021/acs.jproteome.9b00260pt_BR
dc.contributor.externalUniversidade de São Paulo (USP)¦¦Brasilpt_BR
dc.publisher.cityWashingtonpt_BR
dc.identifier.citationvolume18pt_BR
dc.identifier.citationissue10pt_BR
dc.subject.keywordgenomic instabilitypt_BR
dc.subject.keywordCdc42pt_BR
dc.subject.keywordultraviolet radiationpt_BR
dc.subject.keywordaffinity purificationpt_BR
dc.subject.keywordmass spectrometrypt_BR
dc.subject.keywordinteractomept_BR
dc.subject.keywordprotein-protein interactionpt_BR
dc.relation.ispartofabbreviatedJ. proteome res.pt_BR
dc.identifier.citationabntv. 18, n. 10, p. 3597-3614, sep. 2019pt_BR
dc.identifier.citationvancouver2019 Sep;18(10):3597-3614pt_BR
dc.publisher.countryUnited Statespt_BR
dc.contributor.butantanIwai, Leo Kei|:Pesquisador:Docente Colaborador PPGTOX|:Laboratório Especial de Toxinologia Aplicada (LETA)|:pt_BR
dc.contributor.butantanKitano, Eduardo Shigueo|:Aluno|:Laboratório Especial de Toxinologia Aplicada (LETA)|:pt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)¦¦230420/2016/7pt_BR
dc.sponsorship.butantanCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)¦¦88887.136364/2017-00pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2008/58264-5pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2015/03983-0pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2018/01753-6pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2013/07467-1pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
item.openairetypeArticle-
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item.grantfulltextembargo_29990101-
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