These authors contributed equally to this work.
CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
Article first published online: 14 JUN 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 7, pages 1067–1086, July 2013
How to Cite
Cepeda, D., Ng, H.-F., Sharifi, H. R., Mahmoudi, S., Cerrato, V. S., Fredlund, E., Magnusson, K., Nilsson, H., Malyukova, A., Rantala, J., Klevebring, D., Viñals, F., Bhaskaran, N., Zakaria, S. M., Rahmanto, A. S., Grotegut, S., Nielsen, M. L., Szigyarto, C. A.-K., Sun, D., Lerner, M., Navani, S., Widschwendter, M., Uhlén, M., Jirström, K., Pontén, F., Wohlschlegel, J., Grandér, D., Spruck, C., Larsson, L.-G. and Sangfelt, O. (2013), CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. EMBO Mol Med, 5: 1067–1086. doi: 10.1002/emmm.201202341
- Issue published online: 3 JUL 2013
- Article first published online: 14 JUN 2013
- Manuscript Accepted: 10 MAY 2013
- Manuscript Revised: 9 MAY 2013
- Manuscript Received: 6 DEC 2012
- Swedish Cancer Society
- Breast cancer;
- F-box protein;
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.