期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 51, 页码 18562-18566出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503886102
关键词
retinoblastoma protein; oncogenic viruses; tumor suppressor; cell cycle; ubiquitin-protein ligases
资金
- NCI NIH HHS [R01 CA072150, R29 CA072150, CA72150-07, CA91792-01, R01 CA091792] Funding Source: Medline
- NIDCR NIH HHS [R01 DE014136, DE14136-01] Funding Source: Medline
Epstein-Barr virus (EBV) stimulates the proliferation of latently infected B cells and promotes lymphoid malignancies in humans. To address the role of EBV latency protein Epstein-Barr nuclear antigen 3C [EBNA3C) in regulation of the retinoblastoma protein (Rb), we transfected EBNA3C into 293, BJAB, and SAOS-2 cells. In this context, a dominant effect of EBNA3C is to decrease Rb protein levels. EBNA3C also rescues an Rb-incluced flat cell phenotype and targets Rb for proteasome- and ubiquitin-dependent degradation. Further, EBNA3C forms a stable complex with Rb in cells when the proteasome machinery is inhibited and interacts with Rb in vitro, mapping to a conserved domain at the terminus of EBNA3C. Deletion analysis of EBNA3C identified a motif within amino acids 140-149 important for both the binding and regulation of Rb. This motif is of particular interest, because it has also been linked to regulation of the Skp1/Cul1/F-box complex, SCFSkp2. Indeed, inhibition of Skp2 function with a dominant-negative molecule reduces the ability of EBNA3C to degrade Rb. Skp2 has no detectable effect on Rb levels in the absence of EBNA3C, suggesting that SCFSkp2 is specifically usurped by EBNA3C for the enhancement of Rb degradation. That EBNA3C has exploited this association suggests that other human malignancies might use a similar strategy to regulate the Rb protein.
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