βTrCP regulates BMI1 protein turnover via ubiquitination and degradation

Cell Cycle. 2011 Apr 15;10(8):1322-30. doi: 10.4161/cc.10.8.15372. Epub 2011 Apr 15.

Abstract

The polycomb group protein BMI1 has been linked to proliferation, senescence, cancer progression and stem cell phenotype. At present, very little is known about its regulation. Here, we report that BMI1 contains a functional recognition motif for the F box protein βTrCP, which regulates ubiquitination and proteasome-mediated degradation of various proteins. We show that overexpression of wild-type βTrCP but not the ΔF mutant of it promotes BMI1 ubiquitination and degradation, and knockdown of βTrCP results in increased expression of BMI1. Furthermore, a mutant of BMI1 with an altered βTrCP recognition motif is much more stable than wild-type BMI1. We also show that wild-type BMI1 but not the mutant BMI1 interacts with βTrCP. Accordingly, compared to wild-type BMI1, mutant protein exhibited increased pro-oncogenic activity. In summary, our findings suggest that βTrCP regulates turnover of BMI1 and its function relevant to oncogenesis, cellular senescence and aging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cellular Senescence / genetics
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression
  • Gene Silencing
  • Humans
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Polycomb Repressive Complex 1
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / genetics
  • Protein Interaction Domains and Motifs / genetics
  • Protein Stability
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Retroviridae
  • Transfection
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins / antagonists & inhibitors
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • BMI1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Polycomb Repressive Complex 1
  • Proteasome Endopeptidase Complex