Productive human herpesvirus 6 infection causes aberrant accumulation of p53 and prevents apoptosis.
p53 plays an important role in tumour suppression in cells exposed to some genotoxic stresses. We found that the p53 protein level was increased in a variety of cell lines infected with human herpesvirus 6 (HHV-6). Because the elevation in p53 began very soon after infection (4 h) and did not occur with UV-inactivated virus infection, it appeared to require the expression of one or more viral immediate-early (IE) genes. To elucidate the mechanism of p53 induction, we investigated its regulation at the protein level. Pulse-chase analysis showed that the stability of p53 increased in HHV-6-infected cells. In addition, the ubiquitination of p53 decreased after infection, indicating that the stability of p53 was increased through deubiquitination. We showed by confocal microscopy that the additional p53 mainly localized to the cytoplasm and that p53 was retained in the cytoplasm even after UV irradiation, but that it translocated into the nucleus in mock-infected cells. Furthermore, DNA fragmentation analysis, a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay and annexin V staining showed that infected cells were resistant to UV-induced apoptosis. These results lead us to propose that HHV-6 has a mechanism for retaining p53 within the cytoplasm and protects the infected cells from apoptosis.
Takemoto
Masaya
M
Department of Microbiology, Osaka University Medical School C1, 2-2 Yamada-Oka Suita, Osaka 565-0871, Japan.
Mori
Yasuko
Y
Department of Microbiology, Osaka University Medical School C1, 2-2 Yamada-Oka Suita, Osaka 565-0871, Japan.
Ueda
Keiji
K
Department of Microbiology, Osaka University Medical School C1, 2-2 Yamada-Oka Suita, Osaka 565-0871, Japan.
Kondo
Kazuhiro
K
Department of Microbiology, Osaka University Medical School C1, 2-2 Yamada-Oka Suita, Osaka 565-0871, Japan.
Yamanishi
Koichi
K
Department of Microbiology, Osaka University Medical School C1, 2-2 Yamada-Oka Suita, Osaka 565-0871, Japan.
D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001483:Base Sequence; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D004355:Drug Stability; D015870:Gene Expression; D017781:Genes, Immediate-Early; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D004279:DNA, Viral; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin