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

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.

Pubmed ID: 16337594

Authors

  • Sdek P
  • Ying H
  • Chang DL
  • Qiu W
  • Zheng H
  • Touitou R
  • Allday MJ
  • Xiao ZX

Journal

Molecular cell

Publication Data

December 9, 2005

Associated Grants

  • Agency: NCPDCID CDC HHS, Id: NIH/NCI79804

Mesh Terms

  • Cell Line, Tumor
  • Cysteine Endopeptidases
  • DNA
  • Gamma Rays
  • Humans
  • In Vitro Techniques
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein
  • S Phase
  • Ubiquitin