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Title: | CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer |
Author: | Cepeda, Diana Ng, Hwee-Fang Sharifi, Hamid Reza Mahmoudi, Salah Soto Cerrato, Vanessa Fredlund, Erik Magnusson, Kristina Nilsson, Helen Malyukova, Alena Rantala, Juha Klevebring, Daniel Viñals Canals, Francesc Bhaskaran, Nimesh Zakaria, Siti Mariam Rahmanto, Aldwin Suryo Grotegut, Stefan Nielsen, Michael Lund Szigyarto, Cristina Al-Khalili Sun, Dahui Lerner, Mikael Navani, Sanjay Widschwendter, Martin Uhlén, Mathias Jirström, Karin Pontén, Fredrik Wohlschlegel, James Grandér, Dan Spruck, Charles Larsson, Lars-Gunnar Sangfelt, Olle |
Keywords: | Càncer de mama Ubiqüitina Proteïnes quinases Cicle cel·lular Breast cancer Ubiquitin Protein kinases Cell cycle |
Issue Date: | Jul-2013 |
Publisher: | EMBO Press |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1002/emmm.201202341 |
It is part of: | EMBO Molecular Medicine, 2013, vol. 5, num. 7, p. 1067-1086 |
URI: | http://hdl.handle.net/2445/120581 |
Related resource: | https://doi.org/10.1002/emmm.201202341 |
ISSN: | 1757-4676 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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