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

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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/120581
Acceso en línea:https://hdl.handle.net/2445/120581
Access Level:acceso abierto
Palabra clave:Càncer de mama
Ubiqüitina
Proteïnes quinases
Cicle cel·lular
Breast cancer
Ubiquitin
Protein kinases
Cell cycle
Descripción
Sumario: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.

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