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AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway

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dc.contributor.author Pérez García, Arantxa
dc.contributor.author Pérez Durán, Pablo
dc.contributor.author Wossning, Thomas
dc.contributor.author Sernandez, Isora V.
dc.contributor.author Mur, Sonia M.
dc.contributor.author Cañamero, Marta
dc.contributor.author Real, Francisco X.
dc.contributor.author Ramiro, Almudena R.
dc.date.accessioned 2016-04-26T12:44:39Z
dc.date.available 2016-04-26T12:44:39Z
dc.date.issued 2015
dc.identifier.citation Pérez-García A, Pérez-Durán P, Wossning T, Sernandez IV, Mur SM, Cañamero M et al. AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway. EMBO molecular medicine. 2015;7(10):1327-36. DOI: 10.15252/emmm.201505348
dc.identifier.issn 1757-4676
dc.identifier.uri http://hdl.handle.net/10230/26172
dc.description.abstract Activation-induced deaminase (AID) initiates secondary antibody diversification in germinal center B cells, giving rise to higher affinity antibodies through somatic hypermutation (SHM) or to isotype-switched antibodies through class switch recombination (CSR). SHM and CSR are triggered by AID-mediated deamination of cytosines in immunoglobulin genes. Importantly, AID activity in B cells is not restricted to Ig loci and can promote mutations and pro-lymphomagenic translocations, establishing a direct oncogenic mechanism for germinal center-derived neoplasias. AID is also expressed in response to inflammatory cues in epithelial cells, raising the possibility that AID mutagenic activity might drive carcinoma development. We directly tested this hypothesis by generating conditional knock-in mouse models for AID overexpression in colon and pancreas epithelium. AID overexpression alone was not sufficient to promote epithelial cell neoplasia in these tissues, in spite of displaying mutagenic and genotoxic activity. Instead, we found that heterologous AID expression in pancreas promotes the expression of NKG2D ligands, the recruitment of CD8(+) T cells, and the induction of epithelial cell death. Our results indicate that AID oncogenic potential in epithelial cells can be neutralized by immunosurveillance protective mechanisms.
dc.description.sponsorship AP‐G is a fellow of the research training program (FPU‐ AP2009‐1732) funded by the Ministerio de Educación, Cultura y Deporte, PP‐D was an FPI fellow from the Ministerio de Ciencia e Innovación. ARR is supported by Centro Nacional de Investigaciones Cardiovaculares (CNIC). This work was funded by grants from the Ministerio de Economía y Competitividad (SAF2010‐21394, SAF2013‐42767‐R) and the European Research Council Starting Grant program (BCLYM‐207844) to ARR. The CNIC is supported by the Ministerio de Economía y Competitividad and the Pro‐CNIC Foundation. FXR is supported by SAF2011‐29530 and ONCOBIO Consolider grants from Ministerio de Economía y Competitividad (Madrid, Spain), RTICC from Instituto de Salud Carlos III, and grant 256974 from European Union Seventh Framework Programme to FXR.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley-Blackwell
dc.relation.ispartof EMBO molecular medicine. 2015;7(10):1327-36
dc.rights © 2015 The Authors. Published under the terms of the CC BY 4.0 license
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.other Pàncrees -- Càncer
dc.subject.other Epiteli -- Càncer
dc.title AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.15252/emmm.201505348.
dc.subject.keyword NKG2D
dc.subject.keyword Activation‐induced deaminase
dc.subject.keyword Cancer
dc.subject.keyword Epithelium
dc.subject.keyword Pancreas
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010‐21394
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013‐42767‐R
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011‐29530
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/207844
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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