title: CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer.
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. 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.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Cepeda
authors.forename: Hwee-Fang
authors.initials: HF
authors.lastname: Ng
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Sharifi
authors.forename: Salah
authors.initials: S
authors.lastname: Mahmoudi
authors.forename: Vanessa Soto
authors.initials: VS
authors.lastname: Cerrato
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.forename: Kristina
authors.initials: K
authors.lastname: Magnusson
authors.forename: Helén
authors.initials: H
authors.lastname: Nilsson
authors.forename: Alena
authors.initials: A
authors.lastname: Malyukova
authors.forename: Juha
authors.initials: J
authors.lastname: Rantala
authors.forename: Daniel
authors.initials: D
authors.lastname: Klevebring
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.forename: Nimesh
authors.initials: N
authors.lastname: Bhaskaran
authors.forename: Siti Mariam
authors.initials: SM
authors.lastname: Zakaria
authors.forename: Aldwin Suryo
authors.initials: AS
authors.lastname: Rahmanto
authors.forename: Stefan
authors.initials: S
authors.lastname: Grotegut
authors.forename: Michael Lund
authors.initials: ML
authors.lastname: Nielsen
authors.forename: Cristina Al-Khalili
authors.initials: CA
authors.lastname: Szigyarto
authors.forename: Dahui
authors.initials: D
authors.lastname: Sun
authors.forename: Mikael
authors.initials: M
authors.lastname: Lerner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Navani
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlén
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: James
authors.initials: J
authors.lastname: Wohlschlegel
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Charles
authors.initials: C
authors.lastname: Spruck
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
mesh_terms: D000595:Amino Acid Sequence; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; 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 / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D015533:Transcriptional Activation; D054875:Ubiquitination
chemical_list: D016271:Proto-Oncogene Proteins c-myc; C584002:FBXO28 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2
keywords: Breast cancer; CDK; F-box protein; FBXO28; MYC