Title | MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Sdek P, Ying H, Chang DLF, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao Z-XJim |
Journal | Mol Cell |
Volume | 20 |
Issue | 5 |
Pagination | 699-708 |
Date Published | 2005 Dec 09 |
ISSN | 1097-2765 |
Keywords | 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 |
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. |
DOI | 10.1016/j.molcel.2005.10.017 |
Alternate Journal | Mol Cell |
PubMed ID | 16337594 |
Grant List | NIH/NCI79804 / CI / NCPDCID CDC HHS / United States |
Related Faculty:
Hongwu Zheng, Ph.D.