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000130382 0247_ $$2ISSN$$a1460-2075
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000130382 1001_ $$00000-0002-4593-286X$$aSuryo Rahmanto, Aldwin$$b0
000130382 245__ $$aFBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.
000130382 260__ $$aHeidelberg$$bEMBO Press$$c2016
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000130382 520__ $$aSOX9 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.
000130382 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000130382 650_7 $$2NLM Chemicals$$a4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide
000130382 650_7 $$2NLM Chemicals$$aAZD2014
000130382 650_7 $$2NLM Chemicals$$aAZD8186
000130382 650_7 $$2NLM Chemicals$$aAniline Compounds
000130382 650_7 $$2NLM Chemicals$$aCell Cycle Proteins
000130382 650_7 $$2NLM Chemicals$$aChromones
000130382 650_7 $$2NLM Chemicals$$aF-Box Proteins
000130382 650_7 $$2NLM Chemicals$$aMorpholines
000130382 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000130382 650_7 $$2NLM Chemicals$$aPyrimidines
000130382 650_7 $$2NLM Chemicals$$aPyrroles
000130382 650_7 $$2NLM Chemicals$$aSOX9 Transcription Factor
000130382 650_7 $$2NLM Chemicals$$aSOX9 protein, human
000130382 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000130382 650_7 $$0EC 2.7.1.-$$2NLM Chemicals$$aPhosphatidylinositol 3-Kinases
000130382 650_7 $$0EC 2.7.1.1$$2NLM Chemicals$$aMTOR protein, human
000130382 650_7 $$0EC 2.7.1.1$$2NLM Chemicals$$aTOR Serine-Threonine Kinases
000130382 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProto-Oncogene Proteins c-akt
000130382 650_7 $$0EC 2.7.11.26$$2NLM Chemicals$$aGlycogen Synthase Kinase 3
000130382 650_7 $$0EC 6.3.2.19$$2NLM Chemicals$$aFBXW7 protein, human
000130382 650_7 $$0Q20Q21Q62J$$2NLM Chemicals$$aCisplatin
000130382 7001_ $$aSavov, Vasil$$b1
000130382 7001_ $$aBrunner, Andrä$$b2
000130382 7001_ $$aBolin, Sara$$b3
000130382 7001_ $$aWeishaupt, Holger$$b4
000130382 7001_ $$aMalyukova, Alena$$b5
000130382 7001_ $$aRosén, Gabriela$$b6
000130382 7001_ $$aČančer, Matko$$b7
000130382 7001_ $$0P:(DE-He78)81d14a5d74f69c16e5e1cd0144cd955c$$aHutter, Sonja$$b8$$udkfz
000130382 7001_ $$aSundström, Anders$$b9
000130382 7001_ $$0P:(DE-He78)0ac2bd1a9fb1823a351ee4434d80808b$$aKawauchi, Daisuke$$b10$$udkfz
000130382 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b11$$udkfz
000130382 7001_ $$aSpruck, Charles$$b12
000130382 7001_ $$aTaylor, Michael D$$b13
000130382 7001_ $$aCho, Yoon-Jae$$b14
000130382 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b15$$udkfz
000130382 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b16$$udkfz
000130382 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b17$$udkfz
000130382 7001_ $$00000-0002-8460-4367$$aSwartling, Fredrik J$$b18
000130382 7001_ $$00000-0002-0316-0195$$aSangfelt, Olle$$b19
000130382 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.201693889$$gVol. 35, no. 20, p. 2192 - 2212$$n20$$p2192 - 2212$$tThe EMBO journal$$v35$$x1460-2075$$y2016
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