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

Research output: Contribution to journalArticle

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. 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.

Details

Authors
  • Diana Cepeda
  • Hwee-Fang Ng
  • Hamid Reza Sharifi
  • Salah Mahmoudi
  • Vanessa Soto Cerrato
  • Erik Fredlund
  • Kristina Magnusson
  • Helen Nilsson
  • Alena Malyukova
  • Juha Rantala
  • Daniel Klevebring
  • Francesc Vinals
  • Nimesh Bhaskaran
  • Siti Mariam Zakaria
  • Aldwin Suryo Rahmanto
  • Stefan Grotegut
  • Michael Lund Nielsen
  • Cristina Al-Khalili Szigyarto
  • Dahui Sun
  • Mikael Lerner
  • Sanjay Navani
  • Martin Widschwendter
  • Mathias Uhlen
  • Fredrik Ponten
  • James Wohlschlegel
  • Dan Grander
  • Charles Spruck
  • Lars-Gunnar Larsson
  • Olle Sangfelt
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Breast cancer, CDK, F-box protein, FBXO28, MYC
Original languageEnglish
Pages (from-to)1067-1086
JournalEMBO Molecular Medicine
Volume5
Issue number7
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Pathology, (Lund) (013030000)