CDK-mediated activation of the SCF(FBXO) (28) 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. 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.
['Cepeda|Diana|D|', 'Ng|Hwee-Fang|HF|', 'Sharifi|Hamid Reza|HR|', 'Mahmoudi|Salah|S|', 'Cerrato|Vanessa Soto|VS|', 'Fredlund|Erik|E|', 'Magnusson|Kristina|K|', 'Nilsson|Helén|H|', 'Malyukova|Alena|A|', 'Rantala|Juha|J|', 'Klevebring|Daniel|D|', 'Viñals|Francesc|F|', 'Bhaskaran|Nimesh|N|', 'Zakaria|Siti Mariam|SM|', 'Rahmanto|Aldwin Suryo|AS|', 'Grotegut|Stefan|S|', 'Nielsen|Michael Lund|ML|', 'Szigyarto|Cristina Al-Khalili|CA|', 'Sun|Dahui|D|', 'Lerner|Mikael|M|', 'Navani|Sanjay|S|', 'Widschwendter|Martin|M|', 'Uhlén|Mathias|M|', 'Jirström|Karin|K|', 'Pontén|Fredrik|F|', 'Wohlschlegel|James|J|', 'Grandér|Dan|D|', 'Spruck|Charles|C|', 'Larsson|Lars-Gunnar|LG|', 'Sangfelt|Olle|O|']
D000595:Amino Acid Sequence D001940:Breast D001943:Breast Neoplasms D016203:CDC2 Protein Kinase D045744:Cell Line, Tumor D049109:Cell Proliferation D051357:Cyclin-Dependent Kinase 2 D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008969:Molecular Sequence Data D010766:Phosphorylation D011379:Prognosis D011401:Promoter Regions, Genetic D059748:Proteolysis D016271:Proto-Oncogene Proteins c-myc D044843:SKP Cullin F-Box Protein Ligases D015398:Signal Transduction D016019:Survival Analysis D015533:Transcriptional Activation D054875:Ubiquitination
Breast cancer F-box protein FBXO28 MYC CDK