Targeting retinoblastoma protein for degradation by proteasomes.
Inactivation of retinoblastoma protein (Rb) plays a key role in human tumorigenesis. Although the regulation of Rb by phosphorylation has been extensively studied, the regulation of proteasome-mediated Rb protein degradation is largely unknown. Viral oncoprotein E7, Epstein-Barr virus nuclear antigen 3C (EBNA3C), human cytomegalovirus pp71 and cellular oncoprotein gankyrin all contain the L-x-C-x-E Rb-binding motif and target Rb protein for degradation in either ubiquitin-dependent or ubiquitin-independent proteasome pathways. The molecular mechanisms, however, remain elusive. The MDM2 oncoprotein is overexpressed in a variety of human cancers. MDM2 functions as an ubiquitin E3 ligase and induces p53 protein degradation through ubiquitination-proteasome pathway. Both MDM2 central acidic domain and the C-terminal RING domain are critical for p53 degradation. MDM2 also interacts with Rb through its central acidic domain and inhibits Rb function in part by blocking Rb-E2F-DNA complex formation. Recently, we showed that MDM2 binds to C8 subunit of 20S proteasome and promotes Rb-C8 interaction, leading to a proteasome-dependent ubiquitin-independent degradation of Rb. Knockdown of MDM2 results in accumulation of hypophosphorylated Rb and inhibition of DNA synthesis. Taken together, we suggest that targeting Rb protein for degradation by proteasomes may represent a common neoplastic strategy during human cancer development.
Ying
Haoqiang
H
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Xiao
Zhi-Xiong J
ZX
D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*
D016160:Retinoblastoma Protein; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex