Transient increases in p53-responsible gene expression at early stages of Epstein-Barr virus productive replication.
Expression of Epstein-Barr Virus BZLF1, a key protein initiating the switch from latent to lytic infection, is known to cause cell growth arrest by accumulating p53 and p21(WAF1/CIP1) in epithelial cells, but its molecular mechanism remains elusive. We found here that the BZLF1 protein stimulates p53 binding to its recognition sequence. The BZLF1 accelerated the rate of p53-DNA complex formation through the interaction with p53 protein and also enhanced p53-specific transcription in vitro. Furthermore, p53 protein was found to bind to its target promoter regions specifically in the early stages of lytic replication. Overexpression of p53 at the early stages of lytic replication enhanced viral genome replication, supporting the idea that p53 plays an important role in the initiation steps of EBV replication. Taking the independent role of BZLF1 on p53 degradation into consideration, we propose that the BZLF1 protein regulates p53 and its target gene products in two distinctive manners; transient induction of p53 at the early stages for the initiation of viral productive replication and p53 degradation at the later stages for S-phase like environment preferable for viral replication.
Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
Yoshitaka
Y
Sato
Noriko
N
Shirata
Takayuki
T
Murata
Sho
S
Nakasu
Ayumi
A
Kudoh
Satoko
S
Iwahori
Sanae
S
Nakayama
Shigeki
S
Chiba
Hiroki
H
Isomura
Teru
T
Kanda
Tatsuya
T
Tsurumi
D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014779:Virus Replication
C063676:BZLF1 protein, Herpesvirus 4, Human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53