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Journal of Virology, February 2002, p. 1077-1088, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1077-1088.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Cyclin-Dependent Kinase Inhibitor Roscovitine Inhibits the Transactivating Activity and Alters the Posttranslational Modification of Herpes Simplex Virus Type 1 ICP0

David J. Davido,1,{dagger} David A. Leib,2 and Priscilla A. Schaffer1*

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076,1 Department of Ophthalmology and Visual Science and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-80962

Received 21 September 2001/ Accepted 15 October 2001

The cyclin-dependent kinase (cdk) inhibitor Roscovitine (Rosco) reduces transcription of herpes simplex virus early genes significantly, even in the presence of wild-type levels of immediate-early (IE) viral proteins, suggesting that the transactivating functions of IE proteins may require the activities of one or more Rosco-sensitive cdk (L. M. Schang, A. Rosenberg, and P. A. Schaffer, J. Virol. 73:2161–2172, 1999). Based on this observation, we sought to determine whether Rosco alters the transactivating activity and posttranslational modification state of the IE protein, infected cell protein 0 (ICP0), in KOS6ß-infected Vero cells. KOS6ß is a KOS-derived recombinant virus containing an ICP0-inducible ICP6 promoter::lacZ cassette. To monitor ICP0’s transactivating activity, KOS6ß-infected cells were released from a cycloheximide (CHX)-mediated protein synthesis block into medium with or without Rosco, and ß-galactosidase activity was measured. Rosco inhibited the ability of ICP0 to transactivate the ICP6 promoter by 50-fold. This inhibition was shown not to be a consequence of inhibition of ICP6 basal promoter activity or aberrant nuclear localization of ICP0. Rosco also altered the electrophoretic mobility of a portion of ICP0 molecules derived from KOS-infected cells following reversal of a CHX block. Notably, however, Rosco had only a minimal effect on the phosphorylation state of ICP0. We conclude that ICP0’s transactivating activity requires Rosco-sensitive cdks and hypothesize that these cdks regulate the functions of cellular enzymes which modify ICP0, and are, consequently, required for its transactivating activity. Thus, we propose that Rosco regulates ICP0’s posttranslational state by mechanisms other than, or in addition to, phosphorylation.

* Corresponding author. Present address: Department of Medicine, Harvard Medical School at the Beth Israel Deaconess Medical Center, 330 Brookline Ave., RN 123, Boston, MA 02215. Phone: (617) 667-2958. Fax: (617) 667-8540. E-mail: pschaffe{at}caregroup.harvard.edu.

{dagger} Present address: Department of Medicine, Harvard Medical School at the Beth Israel Deaconess Medical Center, Boston, MA 02215.

Journal of Virology, February 2002, p. 1077-1088, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1077-1088.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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