CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
| Autor: | 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, Vinals, 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, Uhlen, Mathias, Jirstrom, Karin, Pontén, Fredrik, Wohlschlegel, James, Grander, Dan, Spruck, Charles, Larsson, Lars-Gunnar, Sangfelt, Olle |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Transcriptional Activation
Medicin och hälsovetenskap F-box protein CDK Molecular Sequence Data Breast Neoplasms MYC Medical and Health Sciences Proto-Oncogene Proteins c-myc Breast cancer Cell Line Tumor CDC2 Protein Kinase FBXO28 Humans Amino Acid Sequence Breast Phosphorylation Promoter Regions Genetic Research Articles Cell Proliferation SKP Cullin F-Box Protein Ligases Cyclin-Dependent Kinase 2 Ubiquitination Prognosis Survival Analysis Gene Expression Regulation Neoplastic Proteolysis Female Signal Transduction |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text