CDK-mediated Activation of the SCF(FBXO) (28) Ubiquitin Ligase Promotes MYC-driven Transcription and Tumourigenesis and Predicts Poor Survival in Breast Cancer

EMBO Mol Med. 2013 Jul;5(7):1067-86. doi: 10.1002/emmm.201202341. Epub 2013 Jun 14.

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.

Keywords: Breast cancer; CDK; F-box protein; FBXO28; MYC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Breast / metabolism
  • Breast / pathology*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Prognosis
  • Promoter Regions, Genetic
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / metabolism*
  • SKP Cullin F-Box Protein Ligases / analysis
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction
  • Survival Analysis
  • Transcriptional Activation
  • Ubiquitination

Substances

  • Proto-Oncogene Proteins c-myc
  • FBXO28 protein, human
  • SKP Cullin F-Box Protein Ligases
  • CDC2 Protein Kinase
  • Cyclin-Dependent Kinase 2