Journal
JOURNAL OF VIROLOGY
Volume 79, Issue 17, Pages 11467-11475Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.79.17.11467-11475.2005
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Funding
- NCI NIH HHS [CA86038, R01 CA086038] Funding Source: Medline
- NHLBI NIH HHS [F31 HL010334, HL 10334-01] Funding Source: Medline
- NIAID NIH HHS [AI56077, R01 AI056077] Funding Source: Medline
- NIDDK NIH HHS [P30 DK032520, DK32520] Funding Source: Medline
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Human cytomegalovirus (HCMV) encodes several proteins that can modulate components of the cell cycle machinery. The UL123 gene product, IE1-72, binds the Rb-related, p107 protein and relieves its repression of E2F-responsive promoters; however, it is unable to induce quiescent cells to enter S phase in wild-type (p53(+/+)) cells. IEl-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IEl-72 may activate the p53 pathway by increasing the levels of p19(Arf) and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IEl-72 expression alone or HCMV infection is found to be dependent on the ataxia-telangiectasia mutated kinase. IE2-86 expression leads to p53 phosphorylation and may contribute to this phenotype in HCMV-infected cells. We also found that IEl-72 promotes p53 nuclear accumulation by abrogating p53 nuclear shuttling. These events result in the stimulation of p53 activity, leading to a p53- and p21-dependent inhibition of cell cycle progression from G(1) to S phase in cells transiently expressing IEl-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell.
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