CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

EMBO Molecular Medicine

Diana Cepeda¹²  Hwee-Fang Ng¹²  Hamid Reza Sharifi⁴  Salah Mahmoudi¹²  Vanessa Soto Cerrato⁹  Erik Fredlund⁴  Kristina Magnusson⁸  Helén Nilsson⁴  Alena Malyukova¹²  Juha Rantala⁵  Daniel Klevebring¹  Francesc Viñals¹⁴  Nimesh Bhaskaran¹²  Siti Mariam Zakaria⁴  Aldwin Suryo Rahmanto¹²  Stefan Grotegut¹⁰  Michael Lund Nielsen²  Cristina Al-Khalili Szigyarto^3,12  Dahui Sun¹⁰  Mikael Lerner^11,12  Sanjay Navani⁸  Martin Widschwendter^7,12  Mathias Uhlén^3,12  Karin Jirström^6,12  Fredrik Pontén⁸  James Wohlschlegel^12,13  Dan Grandér^11,12  Charles Spruck¹⁰  Lars-Gunnar Larsson⁴ 

[1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;NNF Center for Protein Research, Faculty of Health Sciences, Copenhagen, Denmark;Department of Biotechnology, KTH/Alba Nova University Center, Stockholm, Sweden;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Oregon Health and Science University, Knight Cancer Institute, Portland, OR, USA;Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital, Lund, Sweden;Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, United Kingdom;Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden;Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain;Sanford-Burnham Medical Research Institute, La Jolla, CA, USA;Department of Oncology/Pathology, Cancercentrum Karolinska, Karolinska Institutet, Stockholm, Sweden;Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden;Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA;Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat; and Physiological Sciences II Department, Bellvitge Campus, University of Barcelona, Spain

关键词: Breast cancer;    CDK;    F‐box protein;    FBXO28;    MYC;   

DOI  :  10.1002/emmm.201202341

来源: Wiley

【 摘 要 】

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. SCF^FBXO28 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 SCF^FBXO28 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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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