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CDK-mediated activa...
CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
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Cepeda, D. (author)
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Ng, H. -F (author)
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- Sharifi, H. R. (author)
- Karolinska Institutet
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- Mahmoudi, S. (author)
- Karolinska Institutet
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Cerrato, V. S. (author)
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- Fredlund, E. (author)
- Karolinska Institutet
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- Magnusson, Kristina (author)
- Uppsala universitet,Molekylär och morfologisk patologi,Rudbeck Laboratory
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Nilsson, H. (author)
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- Malyukova, A. (author)
- Karolinska Institutet
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Rantala, J. (author)
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- Klevebring, D. (author)
- Karolinska Institutet
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Viñals, F. (author)
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Bhaskaran, N. (author)
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Zakaria, S. M. (author)
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Rahmanto, A. S. (author)
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Grotegut, S. (author)
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Nielsen, M. L. (author)
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- Al-Khalili Szigyarto, Cristina (author)
- KTH,Proteomik och nanobioteknologi
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Sun, D. (author)
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Lerner, M. (author)
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- Navani, S. (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Rudbeck Laboratory
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Widschwendter, M. (author)
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- Uhlén, Mathias (author)
- KTH,Proteomik och nanobioteknologi
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- Jirström, Karin (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Pontén, Fredrik (author)
- Uppsala universitet,Molekylär och morfologisk patologi,Rudbeck Laboratory
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Wohlschlegel, J. (author)
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- Grandér, D. (author)
- Karolinska Institutet
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Spruck, C. (author)
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- Larsson, L. -G (author)
- Karolinska Institutet
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- Sangfelt, O. (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2013-06-14
- 2013
- English.
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 5:7, s. 999-1018
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https://doi.org/10.1...
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https://doi.org/10.1...
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Abstract
Subject headings
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- SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- Breast cancer
- CDK
- F-box protein
- FBXO28
- MYC
- Breast cancer
- CDK
- F-box protein
- FBXO28
- MYC
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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Cepeda, D.
-
Ng, H. -F
-
Sharifi, H. R.
-
Mahmoudi, S.
-
Cerrato, V. S.
-
Fredlund, E.
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show more...
-
Magnusson, Krist ...
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Nilsson, H.
-
Malyukova, A.
-
Rantala, J.
-
Klevebring, D.
-
Viñals, F.
-
Bhaskaran, N.
-
Zakaria, S. M.
-
Rahmanto, A. S.
-
Grotegut, S.
-
Nielsen, M. L.
-
Al-Khalili Szigy ...
-
Sun, D.
-
Lerner, M.
-
Navani, S.
-
Widschwendter, M ...
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Uhlén, Mathias
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Jirström, Karin
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Pontén, Fredrik
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Wohlschlegel, J.
-
Grandér, D.
-
Spruck, C.
-
Larsson, L. -G
-
Sangfelt, O.
-
show less...
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- By the university
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Royal Institute of Technology
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Lund University
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Karolinska Institutet
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Uppsala University