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dc.contributor.authorHill, R.en_US
dc.contributor.authorMadureira, P. A.en_US
dc.contributor.authorFerreira, B.en_US
dc.contributor.authorBaptista, I.en_US
dc.contributor.authorMachado, S.en_US
dc.contributor.authorColaço, L.en_US
dc.contributor.authorDos Santos, M.en_US
dc.contributor.authorLiu, N.en_US
dc.contributor.authorDopazo, A.en_US
dc.contributor.authorUgurel, S.en_US
dc.contributor.authorAdrienn, A.en_US
dc.contributor.authorKiss-Toth, E.en_US
dc.contributor.authorIsbilen, M.en_US
dc.contributor.authorGure, A. O.en_US
dc.contributor.authorLink, W.en_US
dc.date.accessioned2018-04-12T11:08:10Z
dc.date.available2018-04-12T11:08:10Z
dc.date.issued2017en_US
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/11693/37271
dc.description.abstractIntrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.en_US
dc.language.isoEnglishen_US
dc.source.titleNature Communicationsen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/ncomms14687en_US
dc.subjectBenzyloxycarbonylleucylleucylleucinalen_US
dc.subjectBIM proteinen_US
dc.subjectCaspase 3en_US
dc.subjectCCAAT enhancer binding protein alphaen_US
dc.subjectCopanlisiben_US
dc.subjectDacarbazineen_US
dc.subjectDactinomycinen_US
dc.subjectDactolisiben_US
dc.subjectFasLG proteinen_US
dc.subjectFluorouracilen_US
dc.subjectGemcitabineen_US
dc.subjectMammalian target of rapamycin complex 1en_US
dc.subjectMammalian target of rapamycin complex 2en_US
dc.subjectPaclitaxelen_US
dc.subjectPhosphatidylinositol 3 kinaseen_US
dc.subjectProteinen_US
dc.subjectProtein kinase Ben_US
dc.subjectProtein MDM2en_US
dc.subjectProtein p53en_US
dc.subjectProtein serine threonine kinaseen_US
dc.subjectRapamycinen_US
dc.subjectTranscription factor FKHRL1en_US
dc.subjectTranscription factor FOXOen_US
dc.subjectTribbles homologue 2 proteinen_US
dc.subjectTumor necrosis factor related apoptosis inducing liganden_US
dc.subjectUbiquitin protein ligase COP1en_US
dc.subjectUbiquitin protein ligase E3en_US
dc.subjectUnclassified drugen_US
dc.subjectCanceren_US
dc.subjectCells and cell componentsen_US
dc.subjectChemotherapyen_US
dc.subjectDrug resistanceen_US
dc.subjectEenzymeen_US
dc.subjectEnzyme activityen_US
dc.subjectGene expressionen_US
dc.subjectMetabolismen_US
dc.subjectProteinen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectArticleen_US
dc.subjectCancer combination chemotherapyen_US
dc.subjectCancer prognosisen_US
dc.subjectCancer resistanceen_US
dc.subjectCancer survivalen_US
dc.subjectCancer therapyen_US
dc.subjectCell metabolismen_US
dc.subjectCell proliferationen_US
dc.subjectCell survivalen_US
dc.subjectClinical outcomeen_US
dc.subjectColon canceren_US
dc.subjectControlled studyen_US
dc.subjectEnzyme activationen_US
dc.subjectFemaleen_US
dc.subjectHumanen_US
dc.subjectHuman cellen_US
dc.subjectHuman tissueen_US
dc.subjectMalignant neoplasmen_US
dc.subjectMelanomaen_US
dc.subjectMetastatic melanomaen_US
dc.subjectMouseen_US
dc.subjectNonhumanen_US
dc.subjectPancreas canceren_US
dc.subjectProtein expressionen_US
dc.subjectProtein functionen_US
dc.subjectProtein phosphorylationen_US
dc.subjectProtein targetingen_US
dc.subjectRegulatory mechanismen_US
dc.subjectTreatment responseen_US
dc.titleTRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKTen_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Genetics
dc.citation.spage1en_US
dc.citation.epage9en_US
dc.citation.volumeNumber8en_US
dc.identifier.doi10.1038/ncomms14687en_US
dc.publisherNature Publishing Groupen_US
dc.identifier.eissn1077-3118en_US


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