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Journal of Virology, September 2005, p. 11467-11475, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11467-11475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Jonathan P. Castillo,1,{dagger} Fiona M. Frame,2,{dagger} Harry A. Rogoff,1 Mary T. Pickering,2 Andrew D. Yurochko,3 and Timothy F. Kowalik1,2*

Program in Immunology and Virology,1 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,2 Department of Microbiology and Immunology, Center of Molecular and Tumor Virology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 711303

Received 22 November 2004/ Accepted 7 April 2005

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. IE1-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19Arf and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IE1-72 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 IE1-72 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 G1 to S phase in cells transiently expressing IE1-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Phone: (508) 856-6035. Fax: (508) 856-5920. E-mail: timothy.kowalik{at}umassmed.edu.

{dagger} J.P.C. and F.M.F. contributed equally to this study.

Journal of Virology, September 2005, p. 11467-11475, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11467-11475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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