MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein

Mol Cell. 2005 Dec 9;20(5):699-708. doi: 10.1016/j.molcel.2005.10.017.


Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cysteine Endopeptidases / metabolism
  • DNA / biosynthesis
  • DNA / drug effects
  • Gamma Rays
  • Humans
  • In Vitro Techniques
  • Proteasome Endopeptidase Complex / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / pharmacology
  • Proto-Oncogene Proteins c-mdm2 / radiation effects
  • Retinoblastoma Protein / drug effects
  • Retinoblastoma Protein / metabolism*
  • S Phase / physiology
  • S Phase / radiation effects
  • Ubiquitin / metabolism*


  • Retinoblastoma Protein
  • Ubiquitin
  • DNA
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Cysteine Endopeptidases
  • PSMA7 protein, human
  • Proteasome Endopeptidase Complex