EMBO Molecular Medicine (Jun 2013)
CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer
- Diana Cepeda,
- Hwee‐Fang Ng,
- Hamid Reza Sharifi,
- Salah Mahmoudi,
- Vanessa Soto Cerrato,
- Erik Fredlund,
- Kristina Magnusson,
- Helén Nilsson,
- Alena Malyukova,
- Juha Rantala,
- Daniel Klevebring,
- Francesc Viñals,
- Nimesh Bhaskaran,
- Siti Mariam Zakaria,
- Aldwin Suryo Rahmanto,
- Stefan Grotegut,
- Michael Lund Nielsen,
- Cristina Al‐Khalili Szigyarto,
- Dahui Sun,
- Mikael Lerner,
- Sanjay Navani,
- Martin Widschwendter,
- Mathias Uhlén,
- Karin Jirström,
- Fredrik Pontén,
- James Wohlschlegel,
- Dan Grandér,
- Charles Spruck,
- Lars‐Gunnar Larsson,
- Olle Sangfelt
Affiliations
- Diana Cepeda
- Department of Cell and Molecular Biology, Karolinska Institutet
- Hwee‐Fang Ng
- Department of Cell and Molecular Biology, Karolinska Institutet
- Hamid Reza Sharifi
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
- Salah Mahmoudi
- Department of Cell and Molecular Biology, Karolinska Institutet
- Vanessa Soto Cerrato
- Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona
- Erik Fredlund
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
- Kristina Magnusson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
- Helén Nilsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
- Alena Malyukova
- Department of Cell and Molecular Biology, Karolinska Institutet
- Juha Rantala
- Oregon Health and Science University, Knight Cancer Institute
- Daniel Klevebring
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Francesc Viñals
- Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat; and Physiological Sciences II Department, Bellvitge Campus, University of Barcelona
- Nimesh Bhaskaran
- Department of Cell and Molecular Biology, Karolinska Institutet
- Siti Mariam Zakaria
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
- Aldwin Suryo Rahmanto
- Department of Cell and Molecular Biology, Karolinska Institutet
- Stefan Grotegut
- Sanford‐Burnham Medical Research Institute
- Michael Lund Nielsen
- NNF Center for Protein Research, Faculty of Health Sciences
- Cristina Al‐Khalili Szigyarto
- Department of Biotechnology, KTH/Alba Nova University Center
- Dahui Sun
- Sanford‐Burnham Medical Research Institute
- Mikael Lerner
- Department of Oncology/Pathology, Cancercentrum Karolinska, Karolinska Institutet
- Sanjay Navani
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
- Martin Widschwendter
- Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London
- Mathias Uhlén
- Department of Biotechnology, KTH/Alba Nova University Center
- Karin Jirström
- Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital
- Fredrik Pontén
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
- James Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California
- Dan Grandér
- Department of Oncology/Pathology, Cancercentrum Karolinska, Karolinska Institutet
- Charles Spruck
- Sanford‐Burnham Medical Research Institute
- Lars‐Gunnar Larsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
- Olle Sangfelt
- Department of Cell and Molecular Biology, Karolinska Institutet
- DOI
- https://doi.org/10.1002/emmm.201202341
- Journal volume & issue
-
Vol. 5,
no. 7
pp. 1067 – 1086
Abstract
Abstract 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.
Keywords
