MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Academic Article uri icon

Overview

abstract

  • 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 date

  • December 9, 2005

Research

keywords

  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein
  • Ubiquitin

Identity

Scopus Document Identifier

  • 28444437051

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2005.10.017

PubMed ID

  • 16337594

Additional Document Info

volume

  • 20

issue

  • 5