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.
Sdek
Patima
P
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
Ying
Haoqiang
H
Chang
Donny L F
DL
Qiu
Wei
W
Zheng
Hongwu
H
Touitou
Robert
R
Allday
Martin J
MJ
Xiao
Zhi-Xiong Jim
ZX
D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D005720:Gamma Rays; D006801:Humans; D066298:In Vitro Techniques; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism* / Q000494:pharmacology / Q000528:radiation effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*; D016196:S Phase / Q000502:physiology / Q000528:radiation effects; D025801:Ubiquitin / Q000378:metabolism*
D016160:Retinoblastoma Protein; D025801:Ubiquitin; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; C488662:PSMA7 protein, human; D046988:Proteasome Endopeptidase Complex