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Journal of Virology, March 2007, p. 2663-2674, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01733-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Herpesvirus Saimiri STP-A Oncoprotein Utilizes Src Family Protein Tyrosine Kinase and Tumor Necrosis Factor Receptor-Associated Factors To Elicit Cellular Signal Transduction{triangledown}

Maria I. Garcia,1 Joseph Kaserman,1 Young-Hwa Chung,2 Jae U. Jung,1 and Sun-Hwa Lee1*

Department of Microbiology and Molecular Genetics and Division of Tumor Virology, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, Massachusetts 01772-9102,1 College of Nanoscience and Nanotechnology, Department of Nanomedical Engineering, Pusan National University, Pusan, Korea2

Received 10 August 2006/ Accepted 8 December 2006

The saimiri transforming protein oncogene, called STP-A, of herpesvirus saimiri (HVS) subgroup A is not required for viral replication but is required for lymphoid cell immortalization in culture and lymphoma induction in primates. Here we report that STP-A interacts with cellular tumor necrosis factor receptor-associated factors (TRAF2 and TRAF6) and Src family protein tyrosine kinases (SF-PTKs) in a genetically and functionally separable manner and that each interaction constitutively elicits independent cellular signal transduction. The amino-terminal and central proline-rich motifs of STP-A were responsible for TRAF6 and TRAF2 interactions, respectively, and STP-A and TRAF6 interaction contributed to the majority of NF-{kappa}B activation, whereas STP-A and TRAF2 interaction played a minor role in NF-{kappa}B activation. On the other hand, interaction of STP-A with SF-PTKs through its SH2 binding motif effectively elicited AP-1 and NF-AT transcription factor activity. One cellular gene targeted by STP-A is intercellular adhesion molecule 1 (ICAM-1), which participates in a wide range of inflammatory and immune responses. Both TRAF and SF-PTK signal transductions induced by STP-A were required for the marked increase of ICAM-1 expression. These results demonstrate that the viral oncogene STP-A independently targets two vital cellular signaling molecules and that these activities likely contribute to HVS-mediated lymphoid cell immortalization in culture and lymphoma induction in primates.

* Corresponding author. Mailing address: Tumor Virology Division, New England Primate Research Center, Harvard Medical School, P.O. Box 9102, 1 Pine Hill Drive, Southborough, MA 01772-9102. Phone: (508) 786-1499. Fax: (508) 786-1416. E-mail: sun-hwa_lee{at}hms.harvard.edu.

{triangledown} Published ahead of print on 20 December 2006.

Journal of Virology, March 2007, p. 2663-2674, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01733-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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