SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock

Cell. 2007 Jun 15;129(6):1125-40. doi: 10.1016/j.cell.2007.04.039.


SRC-3/AIB1 is an important growth coactivator whose activity should be tightly regulated since excess activation results in oncogenesis. Herein, we provide evidence that coordinated phosphorylation-dependent ubiquitination regulates SRC-3 coactivator activation and transcriptional specificity. We discovered a critical "actron/degron" element in SRC-3 that is required for this phosphorylation-dependent ubiquitination event and identified GSK3 and SCF(Fbw7alpha) as the respective responsible kinase and E3 ubiquitin ligase. Interestingly, despite that SCF(Fbw7alpha) enhances ubiquitination and promotes eventual transcription-coupled degradation of SRC-3 in a phosphorylation- and Fbw7alpha dosage-dependent manner, our results also uncovered a nonproteolytic "activation" code for SRC-3 ubiquitination induced by Fbw7alpha. We propose that ubiquitination of SRC-3 is a phospho-mediated biphasic event and that a transition from multi-(mono)ubiquitination (SRC-3 activation) to long-chain polyubiquitination (SRC-3 degradation) is processive during the transcriptional coactivation of select transcription factors and can serve as a "transcriptional time clock" to control both the activation and the functional lifetime of coactivators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Expression Regulation
  • HeLa Cells
  • Histone Acetyltransferases / metabolism
  • Histone Acetyltransferases / physiology*
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Receptor Coactivator 3
  • Phosphorylation
  • Sequence Homology, Amino Acid
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription, Genetic
  • Ubiquitin / chemistry*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism


  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Trans-Activators
  • Ubiquitin
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • Ubiquitin-Protein Ligases