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      TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT

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      Author
      Hill, R.
      Madureira, P. A.
      Ferreira, B.
      Baptista, I.
      Machado, S.
      Colaço, L.
      Dos Santos, M.
      Liu, N.
      Dopazo, A.
      Ugurel, S.
      Adrienn, A.
      Kiss-Toth, E.
      Isbilen, M.
      Gure, A. O.
      Link, W.
      Date
      2017
      Source Title
      Nature Communications
      Print ISSN
      2041-1723
      Electronic ISSN
      1077-3118
      Publisher
      Nature Publishing Group
      Volume
      8
      Pages
      1 - 9
      Language
      English
      Type
      Article
      Item Usage Stats
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      104
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      Abstract
      Intrinsic 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.
      Keywords
      Benzyloxycarbonylleucylleucylleucinal
      BIM protein
      Caspase 3
      CCAAT enhancer binding protein alpha
      Copanlisib
      Dacarbazine
      Dactinomycin
      Dactolisib
      FasLG protein
      Fluorouracil
      Gemcitabine
      Mammalian target of rapamycin complex 1
      Mammalian target of rapamycin complex 2
      Paclitaxel
      Phosphatidylinositol 3 kinase
      Protein
      Protein kinase B
      Protein MDM2
      Protein p53
      Protein serine threonine kinase
      Rapamycin
      Transcription factor FKHRL1
      Transcription factor FOXO
      Tribbles homologue 2 protein
      Tumor necrosis factor related apoptosis inducing ligand
      Ubiquitin protein ligase COP1
      Ubiquitin protein ligase E3
      Unclassified drug
      Cancer
      Cells and cell components
      Chemotherapy
      Drug resistance
      Eenzyme
      Enzyme activity
      Gene expression
      Metabolism
      Protein
      Animal experiment
      Animal model
      Article
      Cancer combination chemotherapy
      Cancer prognosis
      Cancer resistance
      Cancer survival
      Cancer therapy
      Cell metabolism
      Cell proliferation
      Cell survival
      Clinical outcome
      Colon cancer
      Controlled study
      Enzyme activation
      Female
      Human
      Human cell
      Human tissue
      Malignant neoplasm
      Melanoma
      Metastatic melanoma
      Mouse
      Nonhuman
      Pancreas cancer
      Protein expression
      Protein function
      Protein phosphorylation
      Protein targeting
      Regulatory mechanism
      Treatment response
      Permalink
      http://hdl.handle.net/11693/37271
      Published Version (Please cite this version)
      http://dx.doi.org/10.1038/ncomms14687
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      • Department of Molecular Biology and Genetics 426
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