CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

Research output: Contribution to journalJournal articleResearchpeer-review

  • Diana Cepeda
  • Hwee-Fang Ng
  • Hamid Reza Sharifi
  • Salah Mahmoudi
  • Vanessa Soto Cerrato
  • Erik Fredlund
  • Kristina Magnusson
  • Helén Nilsson
  • Alena Malyukova
  • Juha Rantala
  • Daniel Klevebring
  • Francesc Viñals
  • Nimesh Bhaskaran
  • Siti Mariam Zakaria
  • Aldwin Suryo Rahmanto
  • Stefan Grotegut
  • Cristina Al-Khalili Szigyarto
  • Dahui Sun
  • Mikael Lerner
  • Sanjay Navani
  • Martin Widschwendter
  • Mathias Uhlén
  • Karin Jirström
  • Fredrik Pontén
  • James Wohlschlegel
  • Dan Grandér
  • Charles Spruck
  • Lars-Gunnar Larsson
  • Olle Sangfelt
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.
Original languageEnglish
JournalE M B O Molecular Medicine (Online)
Issue number7
Pages (from-to)1067-1086
Number of pages20
Publication statusPublished - 3 Jul 2013

ID: 57416710