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Expression of Epstein–Barr virus BZLF1 immediate-early protein induces p53 degradation independent of MDM2, leading to repression of p53-mediated transcription

Authors :
Ayumi Kudoh
Noriko Shirata
Hiroki Isomura
Yukihiro Nishiyama
Sanae Nakayama
Satoko Iwahori
Yoshitaka Sato
Takayuki Murata
Tatsuya Tsurumi
Source :
Virology. (1):204-211
Publisher :
Elsevier Inc.

Abstract

The Epstein–Barr virus (EBV) lytic program elicits ATM-dependent DNA damage response, resulting in phosphorylation of p53 at N-terminus, which prevents interaction with MDM2. Nevertheless, p53-downstream signaling is blocked. We found here that during the lytic infection p53 was actively degraded in a proteasome-dependent manner even with a reduced level of MDM2. BZLF1 protein enhanced the ubiquitination of p53 in SaOS-2 cells. The degradation of p53 was observed even in the presence of Nutlin-3, an inhibitor of p53-MDM2 interaction, and also in mouse embryo fibroblasts lacking mdm2 gene, indicating that the BZLF1 protein-induced degradation of p53 was independent of MDM2. Furthermore, Nutlin-3 increased the level of p53 in the latent phase of EBV infection but not in the lytic phase. Although p53 level is regulated by MDM2 in the latent phase, it might be mediated by the BZLF1 protein-associated E3 ubiquitin ligase in the lytic phase for efficient viral propagation.

Details

Language :
English
ISSN :
00426822
Issue :
1
Database :
OpenAIRE
Journal :
Virology
Accession number :
edsair.doi.dedup.....66e43668155e8f3e31a9f93385333ac0
Full Text :
https://doi.org/10.1016/j.virol.2009.03.017