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@ARTICLE{SuryoRahmanto:130382,
      author       = {A. Suryo Rahmanto and V. Savov and A. Brunner and S. Bolin
                      and H. Weishaupt and A. Malyukova and G. Rosén and M.
                      Čančer and S. Hutter$^*$ and A. Sundström and D.
                      Kawauchi$^*$ and D. Jones$^*$ and C. Spruck and M. D. Taylor
                      and Y.-J. Cho and S. Pfister$^*$ and M. Kool$^*$ and A.
                      Korshunov$^*$ and F. J. Swartling and O. Sangfelt},
      title        = {{FBW}7 suppression leads to {SOX}9 stabilization and
                      increased malignancy in medulloblastoma.},
      journal      = {The EMBO journal},
      volume       = {35},
      number       = {20},
      issn         = {1460-2075},
      address      = {Heidelberg},
      publisher    = {EMBO Press},
      reportid     = {DKFZ-2017-05461},
      pages        = {2192 - 2212},
      year         = {2016},
      abstract     = {SOX9 is a master transcription factor that regulates
                      development and stem cell programs. However, its potential
                      oncogenic activity and regulatory mechanisms that control
                      SOX9 protein stability are poorly understood. Here, we show
                      that SOX9 is a substrate of FBW7, a tumor suppressor, and a
                      SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes
                      a conserved degron surrounding threonine 236 (T236) in SOX9
                      that is phosphorylated by GSK3 kinase and consequently
                      degraded by SCF(FBW)(7α) Failure to degrade SOX9 promotes
                      migration, metastasis, and treatment resistance in
                      medulloblastoma, one of the most common childhood brain
                      tumors. FBW7 is either mutated or downregulated in
                      medulloblastoma, and in cases where FBW7 mRNA levels are
                      low, SOX9 protein is significantly elevated and this
                      phenotype is associated with metastasis at diagnosis and
                      poor patient outcome. Transcriptional profiling of
                      medulloblastoma cells expressing a degradation-resistant
                      SOX9 mutant reveals activation of pro-metastatic genes and
                      genes linked to cisplatin resistance. Finally, we show that
                      pharmacological inhibition of PI3K/AKT/mTOR pathway activity
                      destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering
                      medulloblastoma cells sensitive to cytostatic treatment.},
      keywords     = {4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide
                      (NLM Chemicals) / AZD2014 (NLM Chemicals) / AZD8186 (NLM
                      Chemicals) / Aniline Compounds (NLM Chemicals) / Cell Cycle
                      Proteins (NLM Chemicals) / Chromones (NLM Chemicals) / F-Box
                      Proteins (NLM Chemicals) / Morpholines (NLM Chemicals) /
                      Protein Kinase Inhibitors (NLM Chemicals) / Pyrimidines (NLM
                      Chemicals) / Pyrroles (NLM Chemicals) / SOX9 Transcription
                      Factor (NLM Chemicals) / SOX9 protein, human (NLM Chemicals)
                      / Ubiquitin-Protein Ligases (NLM Chemicals) /
                      Phosphatidylinositol 3-Kinases (NLM Chemicals) / MTOR
                      protein, human (NLM Chemicals) / TOR Serine-Threonine
                      Kinases (NLM Chemicals) / Proto-Oncogene Proteins c-akt (NLM
                      Chemicals) / Glycogen Synthase Kinase 3 (NLM Chemicals) /
                      FBXW7 protein, human (NLM Chemicals) / Cisplatin (NLM
                      Chemicals)},
      cin          = {B062 / G380 / L101},
      ddc          = {570},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)G380-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27625374},
      pmc          = {pmc:PMC5069553},
      doi          = {10.15252/embj.201693889},
      url          = {https://inrepo02.dkfz.de/record/130382},
}