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FBW7 suppression le...
FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
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- Rahmanto, Aldwin Suryo (author)
- Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden
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- Savov, Vasil (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Brunner, Andrä (author)
- Karolinska Institutet,Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden
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- Bolin, Sara (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Weishaupt, Holger (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Malyukova, Alena (author)
- Karolinska Institutet,Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden
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- Rosén, Gabriela (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Čančer, Matko (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Hutter, Sonja (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany
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- Sundström, Anders (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Kawauchi, Daisuke (author)
- German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany
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- Jones, David T.W. (author)
- German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany
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- Spruck, Charles (author)
- Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, Tumor Initiat & Maintenance Program, La Jolla, CA USA
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- Taylor, Michael D. (author)
- Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada
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- Cho, Yoon Jae (author)
- Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA USA
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- Pfister, Stefan M. (author)
- German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany
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- Kool, Marcel (author)
- German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany
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- Korshunov, Andrey (author)
- German Canc Consortium DKTK, Heidelberg, Germany; German Canc Res Ctr, Heidelberg, Germany; Univ Heidelberg Hosp, Dept Neuropathol, Heidelberg, Germany
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- Swartling, Fredrik J. (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Sangfelt, Olle (author)
- Karolinska Institutet,Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden
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(creator_code:org_t)
- 2016-09-13
- 2016
- English.
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In: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 35:20, s. 2192-2212
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https://doi.org/10.1...
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Abstract
Subject headings
Close
- 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 SCFFBW7 alpha. 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- FBW7
- SOX9
- Medulloblastoma
- FBXW7
- ubiquitin
- migration
- metastasis
- drug resistance
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Rahmanto, Aldwin ...
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Savov, Vasil
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Brunner, Andrä
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Bolin, Sara
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Weishaupt, Holge ...
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Malyukova, Alena
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show more...
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Rosén, Gabriela
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Čančer, Matko
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Hutter, Sonja
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Sundström, Ander ...
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Kawauchi, Daisuk ...
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Jones, David T.W ...
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Spruck, Charles
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Taylor, Michael ...
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Cho, Yoon Jae
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Pfister, Stefan ...
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Kool, Marcel
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Korshunov, Andre ...
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Swartling, Fredr ...
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Sangfelt, Olle
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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EMBO Journal
- By the university
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Uppsala University
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Karolinska Institutet