MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
2005; Elsevier BV; Volume: 20; Issue: 5 Linguagem: Inglês
10.1016/j.molcel.2005.10.017
ISSN1097-4164
AutoresPatima Sdek, Haoqiang Ying, Donny L.F. Chang, Wei Qiu, Hongwu Zheng, Robert Touitou, Martin J. Allday, Zhi-Xiong Jim Xiao,
Tópico(s)Ocular Oncology and Treatments
ResumoInactivation 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.
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