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Journal of Virology, April 2002, p. 3731-3738, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3731-3738.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Major Immediate-Early Proteins and Simian Virus 40 Large T Antigen Can Inhibit Apoptosis through Activation of the Phosphatidylinositide 3'-OH Kinase Pathway and the Cellular Kinase Akt

Yongjun Yu and James C. Alwine*

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6142

Received 23 October 2001/ Accepted 18 January 2002

The temperature-sensitive cell line ts13 is mutated in CCG1, the gene encoding TAFII250, the largest of the TATA-binding protein-associated factors (TAFs) in TFIID. At the nonpermissive temperature, the temperature-sensitive phenotypes are (i) transcription defects, (ii) cell cycle arrest in G1, and (iii) apoptosis. We previously demonstrated that the human cytomegalovirus (HCMV) major immediate-early proteins (MIEPs) can rescue the transcription defects and inhibit apoptosis at the nonpermissive temperature. In the work presented, we show that activation of the cellular kinase Akt alone can inhibit apoptosis in ts13 cells grown at the nonpermissive temperature. More significantly, we show that the HCMV MIEPs can activate Akt, resulting in the inhibition of apoptosis. In parallel experiments, we found that simian virus 40 (SV40) large T antigen can mediate the same function. These experiments were done by transfecting the HCMV major immediate-early gene or a cDNA encoding T antigen into ts13 cells, and thus neither viral attachment to receptors, viral tegument proteins, nor any other viral protein is required for Akt activation. Akt is activated by the phosphatidylinositide 3'-OH (PI3) kinase pathway. Using a specific inhibitor of PI3 kinase, we show that the ability of the MIEPs and T antigen to activate Akt and inhibit apoptosis is eliminated, suggesting that the viral proteins utilize the PI3 kinase pathway for Akt activation. Transfection of plasmids which express the individual 86-kDa (IEP86; IE2579aa) and 72-kDa (IEP72; IE1491aa) MIEPs indicate that each MIEP could inhibit apoptosis via activation of the PI3 kinase pathway.

* Corresponding author. Mailing address: 314 Biomedical Research Building, 421 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104-6142. Phone: (215) 898-3256. Fax: (215) 573-3888. E-mail: alwine{at}mail.med.upenn.edu.

Journal of Virology, April 2002, p. 3731-3738, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3731-3738.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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