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

Sdek, P., Ying, H. Q., Chang, D. L. F., Qiu, W., Zheng, H. W., Touitou, R., Allday, M. J., Xiao, Z. X. J. (December 2005) MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Molecular Cell, 20 (5). pp. 699-708. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/16337594
DOI: 10.1016/j.molcel.205.10.017

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 p roteaso me-depen dent 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.

Item Type: Paper
Uncontrolled Keywords: RING FINGER MEDIATED SUPPRESSION TUMOR-SUPPRESSOR GAMMA-INTERFERON 20S PROTEASOME ALPHA-SUBUNIT P53 EXPRESSION RB PATHWAY Biochemistry & Molecular Biology Cell Biology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > MDM2
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein ubiquitination
diseases & disorders > cancer > cancer types > retinoblastoma
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: December 2005
Date Deposited: 22 Aug 2014 19:46
Last Modified: 22 Aug 2014 19:46
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30708

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving